WO2003103657A1 - Traitements des maladies neurodegeneratives - Google Patents

Traitements des maladies neurodegeneratives Download PDF

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Publication number
WO2003103657A1
WO2003103657A1 PCT/JP2003/007128 JP0307128W WO03103657A1 WO 2003103657 A1 WO2003103657 A1 WO 2003103657A1 JP 0307128 W JP0307128 W JP 0307128W WO 03103657 A1 WO03103657 A1 WO 03103657A1
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Prior art keywords
group
formula
hydrocarbon
amino
heterocyclic
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PCT/JP2003/007128
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English (en)
Japanese (ja)
Inventor
武藤 進
板井 昭子
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株式会社医薬分子設計研究所
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Application filed by 株式会社医薬分子設計研究所 filed Critical 株式会社医薬分子設計研究所
Priority to US10/516,293 priority Critical patent/US20060035944A1/en
Priority to CA002488979A priority patent/CA2488979A1/fr
Priority to EA200500006A priority patent/EA011707B1/ru
Priority to AU2003242124A priority patent/AU2003242124A1/en
Priority to EP03730838A priority patent/EP1555018A4/fr
Priority to JP2004510776A priority patent/JP4635130B2/ja
Publication of WO2003103657A1 publication Critical patent/WO2003103657A1/fr
Priority to US12/123,934 priority patent/US20080234233A1/en

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    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Definitions

  • the present invention relates to a medicament for preventing and / or treating a neurodegenerative disease such as Alzheimer's disease or epilepsy.
  • a neurodegenerative disease such as Alzheimer's disease or epilepsy.
  • Alzheimer's disease is a neurodegenerative disease including senile dementia.
  • the characteristic pathological changes in the patient's brain include atrophy of the brain due to loss of nerve cells, and neurogens where fibrous substances are accumulated in nerve cells. Fiber alterations, the presence of patchy deposits called senile plaques in large parts of the cerebral cortex.
  • A the protein accumulated in senile plaques
  • it is said that accumulation of ⁇ ⁇ ⁇ ⁇ ] 3 by any cause may be the cause of Alzheimer's disease (amyloid hypothesis).
  • the concentration of A3 in the brain increases and aggregates to form senile plaques, and the aggregated A ⁇ acts on nerve cells to cause neuronal death and neurofibrillary tangles.
  • NF- ⁇ B Nuclear Factor- ⁇ B
  • N-phenylsalicylamide derivative is disclosed as a plant growth inhibitor in U.S. Pat. No. 4,358,443, and as a medicament, European Patent No. 0,221,211.
  • Japanese Patent Application Laid-Open Nos. Sho 62-93929 and U.S. Pat. No. 6,117,859 disclose an anti-inflammatory agent.
  • WO 9/0954 9 9 pamphlet, WO 02/49632 pamphlet, and WO 02/076 918 pamphlet disclose them as NF- ⁇ B inhibitors.
  • WO99 / 64949 / Pamphlet and WO02 / 49632 The use of pamphlet as an anti-Alzheimer's disease drug has also been suggested.
  • N-phenylsalicylamide derivatives are effective in preventing or treating Alzheimer's disease, and AP-1 (Activated Protein-1 1) There is no description of the activation inhibitory effect.
  • AP-1 Active Protein-1 1
  • WO 02/051397 pamphlet discloses N-phenylsalicylamide derivatives as cytokine production inhibitors. Disclosure of the invention
  • An object of the present invention is to provide a medicament for preventing and / or treating Alzheimer's disease or epilepsy.
  • the present inventors have investigated the effects of various N-arylsalicylamide derivatives and their analogs, hydroxyaryl derivatives, on the inhibition of NF- ⁇ ⁇ activation under TNF- ⁇ stimulation and under the effect of NFNF- ⁇ stimulation.
  • As a result of examining the production of AP-1 activation in E. coli by the reporter Atsey method it was found that the compound of the present invention has an AP_1 activation inhibitory activity in addition to an NF- ⁇ B inhibitory action. Based on this finding, the present inventors have confirmed the efficacy of the above compound in a model animal for Alzheimer's disease and epilepsy, and completed the present invention.
  • A represents a hydrogen atom or an acetyl group
  • E is a 2,5-disubstituted or 3,5-disubstituted phenyl group, or a monocyclic or condensed polycyclic heteroaryl group which may have a substituent, provided that the heteroaryl
  • the reel group is composed of 1) a condensed polycyclic heteroaryl group in which the ring directly bonded to one CONH— group in the formula (I) is a benzene ring, 2) an unsubstituted thiazol-2-yl group, and 3) an unsubstituted group.
  • Ring Z is a group represented by the formula —O—A (where A is as defined above) and the formula CONH—E (where E is as defined above).
  • Arene or a substituent which may have a substituent, or a compound of the formula O—A (where A is as defined above) and a formula—CONH—E (where E is as defined above) Represents a heteroarene which may have a substituent in addition to the group represented by), a pharmaceutically acceptable salt thereof, and a hydrate and a hydrate thereof.
  • the present invention provides a medicament for preventing and / or treating Alzheimer's disease, containing a substance selected from the group consisting of solvates as an active ingredient.
  • a compound selected from the group consisting of the compound represented by the general formula (I), a pharmacologically acceptable salt thereof, a hydrate thereof, and a solvate thereof is effectively used.
  • a medicament for preventing and / or treating epilepsy, which is contained as a component, is also provided.
  • Preferred pharmaceuticals of the present invention include:
  • Ring Z is C 6 to C 1 .
  • A is as defined in formula (I)
  • CONH-E where E is defined in formula (I)
  • a pharmacologically acceptable salt thereof, and the above-mentioned medicament comprising, as an active ingredient, a substance selected from the group consisting of hydrates and solvates thereof.
  • Ring Z force S Formula I O—A (where A is as defined in general formula (I)) and Formula I CONH—E (where E is the definition in general formula (I)
  • the above medicine comprising as an active ingredient a substance selected from
  • E is a 2,5-disubstituted phenyl group (at least one of the substituents is a trifluoromethyl group) or a 3,5-disubstituted phenyl group (at least one of the substituents is Is a trifluoromethyl group) and pharmacologically acceptable salts thereof, as well as substances selected from the group consisting of hydrates and solvates thereof as active ingredients
  • a trifluoromethyl group at least one of the substituents is a trifluoromethyl group
  • 3,5-disubstituted phenyl group at least one of the substituents is Is a trifluoromethyl group
  • E is an optionally substituted monocyclic or condensed polycyclic heteroaryl group (provided that the heteroaryl group is (1) a —CO NH— group in the formula (I) Compounds and drugs that are a fused polycyclic heteroaryl group in which the directly linked ring is a benzene ring, (2) an unsubstituted thiazol-12-yl group, and (3) except for an unsubstituted benzothiazole-2) group)
  • (11) E is a 5-membered monocyclic heteroaryl group which may have a substituent (except when the heteroaryl group is an unsubstituted thiazol-2-yl group)
  • a substance selected from the group consisting of a compound, a pharmacologically acceptable salt thereof, and a hydrate and a solvate thereof are exemplified.
  • the present invention provides the use of each of the above-mentioned substances for the manufacture of the above-mentioned medicines (1) to (11). Further, according to the present invention, there is provided a method for preventing and / or treating Alzheimer's disease, comprising a step of administering a prophylactically and / or therapeutically effective amount of each of the above substances to a mammal including human, and a method for treating epilepsy. There is provided a method for prevention and / or treatment, which comprises a step of administering a prophylactic and / or therapeutic effective amount of each of the above substances to a mammal including human. BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a diagram showing the effect of the medicament of the present invention (Compound No. 4) on memory formation dysfunction in Alzheimer's model animals.
  • any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom may be used unless otherwise specified.
  • hydrocarbon group examples include an aliphatic hydrocarbon group, an aryl group, an arylene group, an aralkyl group, a crosslinked cyclic hydrocarbon group, a spirocyclic hydrocarbon group, and a terpene hydrocarbon.
  • aliphatic hydrocarbon group examples include linear or branched monovalent or divalent acyclic groups such as an alkyl group, an alkenyl group, an alkynyl group, an alkylene group, an alkenylene group, and an alkylidene group.
  • Hydrocarbon group saturated or unsaturated monovalent or divalent alicyclic hydrocarbon such as cycloalkyl group, cycloalkenyl group, cycloalkenyl group, cycloalkyl monoalkyl group, cycloalkylene group, cycloalkenylene group, etc. And the like.
  • alkyl group examples include methyl, ethyl, n-propyl, isopropylinole, n-butinole, isoptinole, sec-butynole, tert-butynole, n-pentyl, isopentinole, 2-methylinobutynole, 1-methylbutyl, neopentyl, , 2-Dimethinolepropynole, 1-ethylpropyl, n-hexyl, 4-methinolepentinole, 3-methinolepentyl, 2-methylpentinole, 1-methinolepentyl, 3,3-dimethinolebutinole, 2,2-dimethyl Butyl, 1,1-dimethynolebutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethy / levynole, 1-ethyl, 1,
  • alkenyl group examples include, but are not limited to, Bier, Propylene-l-yl, aryl, isopropenyl, buta-l-l-en-l-yl, butter 2-l-l-n-yl, butter3 —1 1 le, 2—methinoleprop 2—1 l-yl, 1—meth 2-1-Inore, Penter 1-1-Inore, Penter 2-1-Inore, Penta-3-1-Inore, Penter 4-1-Inore, 3-Methyl butter 2- 3-1-1, 3-Methylpter 3--1-1-yl, Hexar 1--1-Inore, Hexar 2--1-1-Inore, Hexar 3--1-1-Inore, to Kisser 4-1-Innole, Hexar 5-1-Innole, 4-Meinole Penter 3-1-1-Nore, 4-Mechinore Penter 3-1-Innore, Heptor 1-In_ 1-Inno
  • alkynyl group examples include, for example, ethur, propane 1 f-n-yl, propane 2-in-n-l, butter 1-in-l-l-inole, buta l-in-l-l-inole, 1-l Mechinore Proper 2-In-1-Inore, Penta 1-in-1-Inore, Penter 4-In-1 Inore, Hexar 1-1-1 ⁇ f In-1 Inore, Hexar 5-In-1-Inle, Hepter 1-1 In-1 1 Innore, Hepter 6—In 1 1 Nore, Otata 1 In 1 1 1 In, 1 Okta 1 7 In, 1 In, 1 Nonin 1 In 1 1 Inil, Nonon 8 In 1 1—Ill, Deca — 1—Illin 1—Ill, Decah 9 Ill—1—Ill, Linda Power 1—Illin 1—Ill, Linda 1 0—Illin 1 Dode Power One One-In-One-One, One-One-
  • alkylene group includes, for example, methylene, ethylene, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,2-diyl, butane-1 1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, 1,1,4,4-tetramethylbutane-1,4-diyl, etc. 8 linear or branched alkylene groups.
  • anolekenylene group examples include, for example, ethen-1,2-zyl, propene-1,3-zinole, butter1-1,1,4-zinole, buta-2-ene-1,4, zyl and 2-methinolepropene 1,3 ginole, penter 2 -1,5 gil, hexa 3 -1,1,6 gil etc. ⁇ . And 6 linear or branched alkylene groups.
  • alkylidene group for example, methylidene, Echiriden, propylidene, isopropylidene, butylidene, pentylidene, and linear or branched alkylidene group of C 1 -C 6, such as cyclohexylidene to.
  • cycloalkyl group for example, cyclopropyl, cyclobutyl, consequent opening Penchinore, Kishinore cyclohexane, heptyl to consequent opening, a cycloalkyl group of C 3 -C 8, such as Shikurookuchiru.
  • cycloalkyl group may be condensed with a benzene ring, a naphthalene ring, or the like.
  • a benzene ring for example, 1-andanyl, 2-indanyl, 1,2,3,4-tetrahydronaphthalene And 1,2,3,4-tetrahydronaphthalene-1-yl and the like.
  • cycloalkenyl group examples include 2-cyclopropene-1-yl, 2-cyclobutene-11-inole, 2-cyclopentene-11-inole, 3-cyclopentene-11-inole, and 2-cyclohexene one 1 Inore, 3- consequent opening hexene one 1-I le, 1-cyclobutene one 1-Inore include shea Kuroarukeniru group C 3 -C 6, such as 1 over cyclopentene one 1 Iru.
  • cycloalkenyl group is condensed with a benzene ring, a naphthalene ring, etc.
  • cycloalkanegenyl group examples include, for example, 2,4-cyclopentanene-1-inole, 2,4-cyclohexanegen_1-inole, 2,5-cyclohexangen-1-yl, and the like. include cycloalkane Genis Le group C 5 -C 6 of.
  • the above “cycloalkaneenyl group” may be condensed with a benzene ring, a naphthalene ring or the like, and examples thereof include groups such as 11-indur and 2-indenyl.
  • cycloalkyl-alkyl group examples include groups in which one hydrogen atom of the “alkyl group” has been substituted with a “cycloalkyl group”. Examples thereof include cyclopropylmethyl, 1-cyclopropynoleethynole, 2-cyclopropynoleethinole, 3-cyclopropyl pill, 4-cyclopropylbutyl, 5-cyclopropylpentyl, 6-cyclopropynolehexynole, cyclopentinolemethinole, cyclopentinolemethyl, cyclopentylmethyl, butylmethyl , cyclopentylmethyl, Kishinoremechiru cyclohexane, to consequent opening Kishirupu port pills, the consequent opening Kishisurebuchinore, Puchinoremechinore to consequent opening, cycloalkyl O Chi le methylate Honoré, C 4 -C 1 4 of consequent opening alkyl primary alkyl of
  • cycloalkylene group examples include, for example, cyclopropane-1,1, -diyl, cyclopropane-1,1,2-diyl, cyclobutane-1,1,1-diyl, cyclobutane-1,1,2-diyl, cyclobutane-1,1,3 —Ginore, 1-Girl, 1-Girl, 1-Girl, 1-Girl, Cyclopentane 1,3-Girl, 1-Girl, 1-Girl, 1-Girl, 1-Girl Diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diynole, cycloheptane-1
  • 1, 1-Jiinore, consequent opening heptane one 1, 2 - Jiiru, cyclooctane one 1, 1 - Jiiru, cyclooctane _ 1, include cycloalkylene group C 3 -C 8, such as 2-Jiiru.
  • cycloalkenedylene group examples include, for example, 2-cyclopropene_1,1-diinole, 2-cyclobutene_1,1jir, 2-cyclopentene1-1,1jir, 3-cyclopentene-1,1,1jir 2-cyclohexene-1,1,2-diene; 2-cyclohexene-1,1,2-diyne; 2-cyclohexene-1,1,4-diyl; 3-cyclohexene-1,1,1-diyl; 1 Shikurobuten one 1, 2-Jiiru, -1-cyclopentene one 1, 2-Jiiru include Shikuroaruke two alkylene groups C 3 -C 6 one 1, etc. 2 _ Jiiru hexene cycloalkyl.
  • aryl group examples include monocyclic or condensed polycyclic aromatic hydrocarbon groups, and examples thereof include C 6 to C 1 such as phenole, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, and acenaphthylenyl. 4 aryl groups.
  • arylene group examples include 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, naphthalene-1,2, diynole, naphthalene-1,3, diyl, Naphthalene-1,4-diyl, naphthalene-1,5-diyl, naphthalene-1,6-dinore, naphthalene-1,7-diyl, naphthalene-1,8-diyl, naphthalene-1,2-diyl, naphthalene _ C 6 of 2,4-diyl, naphthalene-1 2,5-diyl, naphthalene-1 2,6-diyl, naphthalene-1,2,7-diyl, naphthalene-1,2,8-diyl, anthracene-1,4-diyl -C 1 4 of ⁇ Li one alkylene group.
  • one hydrogen atom of the “alkyl group” is replaced with the “aryl group”
  • aryl group such as benzyl, 1-naphthylmethyl, 2-naphthylmethyl, anthracelmethyl, phenanthrenylmethyl, acenaphtyrenylmethyl, diphenylmethinole, 1-phenethyl, 2- 1- (1-naphthyl) ethyl, 1- (2-naphthyl) ethyl, 2- (1-naphthyl) ethyl ⁇ « ⁇ 2— (2-naphthyl) ethyl, 3-phenylphenyl, 3- (1-naphthyl) pu pill, 3-(2-naphthinole) propyl, 4-pheninolebutinole, 4-1 (1-naphthyl) butyl, 4-1 (2-naphthyl) butyl, 5-phen
  • bridged cyclic hydrocarbon group examples include groups such as bicyclo [2.1.0] pentyl, bicyclo [2.2.1] hepti ⁇ ⁇ bicyclo [2.2.1] octyl, adamantyl and the like. No.
  • spirocyclic hydrocarbon group examples include groups such as spiro [3.4] octyl and spiro [4.5] deca 1,6-genyl.
  • terpene-based hydrocarbon examples include groups such as geranyl, neryl, linalyl, phytyl, menthyl, and bornyl.
  • halogenated alkyl group examples include groups in which one hydrogen atom of the “alkyl group” has been replaced with a “halogen atom”.
  • group examples include fluoromethyl, difluoromethyl, trifluorenomethyl, chloromethyl, dichloromethyl, Trichloromethinole, Bromomethinole, Jib-mouth mometinole, Tripromemotine, Eodomethinole, Jodomethyl, Triodomethyl, 2,2,2-Trifluoroethylino, Pentafluorethyl, 3,3,3-Trifluoropropyl, Heptafulol Linear or branched alkyl halides of CiCs substituted with 1 to 13 halogen atoms such as isopropyl, heptafluoroisopropyl, nonafluorobutyl, perfluorohexyl, etc. Groups.
  • heterocyclic group includes, for example, oxygen as an atom (ring atom) constituting a ring system.
  • a monocyclic or fused polycyclic heteroaryl group containing at least one heteroatom selected from atoms, sulfur atoms, nitrogen atoms, etc., and atoms (ring atoms) constituting a ring system ) Is a monocyclic or fused polycyclic non-aromatic heterocyclic group containing at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • Examples of the “monocyclic heteroaryl group” include, for example, 2-furyl, 3-furyl, 2-cheninole, 3-cheninole, 1-pyrrolyl, 2-pyrrolinole, 3-pyrrolinole, 2-oxoxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2_thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1-imidazolyl, 2-imidazolyl Imidazolyl, 4_imidazolyl, 5f midazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5_pyrazolyl, (1,2,3-oxadiazole) 14-yl, (1,2,3-oxadiazole) ) 1-5-yl, (1,2,4-oxadiazole
  • Examples of the “condensed polycyclic heteroaryl group” include, for example, 2-benzofuranol, 3-benzofuranone, 4-benzobranoline, 5-benzofuranone, 6-benzofuranone, 7-benzofuranone, 1-Isobenzofuraninole, 4-Isobenzofuraninole, 5-Isobenzofuranyl, 2-Venzo [b] Cherry, 3-Venzo [b] Chenyl, 4-benzo [b] Chenyl, 5-benzo [b] chenyl, 6-benzo [b] cheninole, 7_ benzo [b] cheninole, 1 benzo [c] cheninole, 4 benzo
  • Examples of the “monocyclic non-aromatic heterocyclic group” include, for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, thiolanyl, 1 _ imidazolidinyl, 2-imidazolidinyl, 4 ⁇ midazolidinyl, 1-virazolidinyl, 3- villazolidinyl, 4- vilazolidinyl, 1-(2-pyrrolinyl), 1-(2-imidazolinyl), 2--(2-imidazolinyl) ), 1- (2-birazolinyl), 3- (2-pyrazolinyl), piperidino, 2-piridininole, 3-piridininole, 4-piridinyl, 1-homopiperidinyl, 2- Saturation of 3- to 7-membered such as tetrahydro
  • “Fused polycyclic non-aromatic heterocyclic group” includes, for example, 2-quinuclidinyl, 2 1 chroma 2, 3 chroma 2, 4 chroma 2, 5 chroma 2, 7 chroma 2, 8 chroma 2, 1 isochrom 2, 3 isochrom 2-norre, 4-isochroma-nore, 5-isochroma-nore, 6-isochroma-nore, 7-isochroma-nore, 8-isochroma-nore, 2-thiothalomaenore, 3-thiochroma-nore, 4-thiochroma-nore, 4-thiochroma-nore, 5-thiothalomare Nore, 6-Chiochromanore, 7-Chloe mouth Nore, 8-Chiochroma nore, 1-Isothiochroma nore, 3-Isothiochroma-nore, 4-Isothiothalomanore, 5-Isothi
  • heterocyclic group in addition to a nitrogen atom having a bond, a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as an atom (ring atom) constituting a ring system.
  • a monocyclic or condensed polycyclic heteroaryl group which may have 3 to 3 types, and an oxygen atom, in addition to a nitrogen atom having a bond, as an atom (ring atom) constituting a ring system
  • a monocyclic or condensed polycyclic non-aromatic heterocyclic group which may have 1 to 3 types of hetero atoms selected from a sulfur atom, a nitrogen atom, etc. is referred to as a "cyclic amino group”.
  • aryl group A general term for “aryl group”, “cycloalkylene group”, “cycloalkenedylene group”, “arylene group”, “bridged cyclic hydrocarbon group”, “spirocyclic hydrocarbon group”, and “heterocyclic group” And referred to as “cyclic group”. Further, among the “cyclic groups”, in particular, “aryl group”, “arylene group”, “monocyclic heteroaryl group”, and “condensed polycyclic heteroaryl group” are collectively referred to as “aromatic ring”. Formula group ".
  • hydrocarbon monooxy group a group in which a hydrogen atom of the “hydroxy group” is substituted by the “hydrocarbon group” can be mentioned.
  • hydrocarbon the same group as the above “hydrocarbon group” Is mentioned.
  • hydrocarbon monooxy group include, for example, aliphatic hydrocarbons such as an alkoxy group (alkyloxy group), an alkenyloxy group, an alkynyloxy group, a cycloalkyloxy group, and a cycloalkyl-alkyloxy group.
  • alkoxy group examples include, for example, methoxy, ethoxy, n -propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentynoleoxy, isopentyl Noreoxy, 2-methylbutoxy, 1-methylbutoxy, neopentyloxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentinoleoxy, 3-methylinopentyloxy Xy, 2-methylinopentynoleoxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy , 2, 3-dimethylbutoxy, 2-ethylbutoxy, 1-ethylbutoxy, 1-ethyl-11-methylpropoxy, n-heptyloxy,
  • alkenyloxy group examples include, for example, bieroxy, (propenyl-1-yl) oxy, aryloxy, isopropenyloxy, (buter-1-enyl) oxy, (buta-2-ene) (11-yl) oxy, (but-3-one _ 1-yl), (2-methylprop 21-yl), xy, (1-methylprop 2--1-) 1 ⁇ f le) oxy, (Penter 1 1 1 -1 yl) oxy,
  • alkynyloxy group examples include, for example, ethuroxy, (prop-1-in-l-yl) oxy, (prop-2-in-l-yl) oxy, (butter-1-in-yl) Oxy, (pter 3 _in 1 -1-yl) oxy, (1 methylprop 2-in 1 -1 yl) (11-yl) oxy, (hex 11-yl), (hex 5-yl) oxy, (hepter 1-1-yl) oxy, (Hepater 6-in-1 1-yl) Oxy, (Okta 1-in-1 11-yl), (Okita 1 7- ⁇ f n-1 11-yl) Oxy, (Non 1 1-in 1 1 —Yil) Oxy, (Non-One 8—In-One) Oxy, (Dekar 1—In-One 1-yl) Oxy, (De 1 9 1 in 1 1-il) Oxy, ( ⁇ ⁇ 1 ⁇ ⁇ 1 _ 1
  • Cycloalkyl one Okishi group for example, cyclopropyl Provo alkoxy, Shikurobu butoxy, consequent opening pliers Honoré oxy, cyclohexane Kishiruokishi, consequent opening Hepuchinoreokishi, cycloalkyl O lipped Ruo carboxymethyl cycloalkyl one C 3 -C 8, such as Okishi Groups.
  • cycloalkyl-alkyl-oxy group examples include, for example, cyclopropylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy, 3-cyclopropylpropoxy, 4-cyclopropylbutoxy, 5-cyclopropylpentyloxy , 6-cyclopropylhexyloxy, cyclobutyl methoxy, cyclopentyl methoxy, cyclopentinolemethoxy, cyclopentinolemethoxy, cyclopentinolemethoxy, cyclohexinolemethoxy, 2-cyclohexinoleethoxy, 3-cyclohexinolepropoxy, 4-cyclohexylbutoxy , Cycloheptinoleme Toxic And C 4 -C 14 cycloalkyl-alkyl-oxy groups such as toxy and 6-cyclooctylhexyloxy.
  • the "Ariru one Okishi group" for example, phenoxy, 1 _ Nafuchiruokishi, 2 Nafuchiruokishi, Antoriruokishi, off Henin tolyl O carboxymethyl include C 6 -C 1 4 of ⁇ Li one Ruokishi group such Asenafuchire Niruokishi.
  • aralkyloxy group examples include, for example, benzyloxy, 1-naphthylmethoxy, 2-naphthylmethoxy, anthracenylmethoxy, phenanthrenylmethoxy, acenaphthylenylmethoxy, diphenylmethoxy, 1-phenyloxy, 2-phenethyloxy, 1- (1-naphthyl) ethoxy, 1_ (2-naphthyl) ethoxy, 2_ (1-naphthyl) ethoxy, 2- (2-naphthyl) ethoxy, 3-_phenylpropoxy, 3-(1-naphthyl) Propoxy, 3- (2-naphthyl) propoxy, 4-phenylbutoxy, 4- (1-naphthinole) butoxy, 4-
  • alkylenedioxy group examples include groups such as methylenedioxy, ethylenedioxy, 1-methylmethylenedioxy, and 1,1-dimethylmethylenedioxy.
  • halogenated alkoxy group examples include groups in which a hydrogen atom of a “hydroxyl group” has been replaced by a “halogenated alkyl group”.
  • heterocyclic oxy group a group in which a hydrogen atom of the “hydroxy group” is substituted with the “heterocyclic group” can be mentioned.
  • heterocyclic group the same group as the above “heterocyclic group” Is mentioned.
  • heterocyclic monooxy group for example, a monocyclic heteroaryloxy group, a condensed polycyclic heteroaryloxy group, a monocyclic non-aromatic heterocyclic monooxy group, a condensed polycyclic non-aromatic And a heterocyclic monooxy group.
  • “Monocyclic heteroaryloxy” includes, for example, 3-Chenyloxy,
  • Examples of the group include (isoxazole-3-inole), (thiazole-41-yl), 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, and (pyrimidine-4-yl) oxy.
  • Examples of the “condensed polycyclic heteroaryloxy group” include groups such as 5-indoloxy, (benzimidazol-2-yl) oxy, 2-quinolyloxy, 3-quinolyloxy, and 4-quinolyloxy.
  • Examples of the “monocyclic non-aromatic heterocyclic monooxy group” include groups such as 3-pyrrolidinyloxy and 4-piperidinyloxy.
  • Examples of the “condensed polycyclic non-aromatic heterocyclic monooxy group” include groups such as 3-indolinyloxy and 4-chromanyloxy.
  • hydrocarbon-sulfanyl group examples include a group in which a hydrogen atom of the “sulfanyl group” is replaced by a “hydrocarbon group”.
  • hydrocarbon the same as the above “hydrocarbon group” Groups.
  • hydrocarbon-sulfanyl group examples include, for example, an alkylulsulfanyl group, an alkenylsulfanyl group, an alkynyl-sulfanyl group, a cycloalkyl-1-sulfanyl group, and a cycloanolexylanoloxylsulfanyl group.
  • alkyl monosulfanyl group examples include, for example, methylsulfanyl, ethylsulfanyl, ⁇ - propinolesnorphaninole, isopropinolesulfaninole, ⁇ - butylsnorephanyl, isobutylsnolephanyl, sec- Butylsulfanyl, t ert butinoresnolephaninole, n-pentylsulfonyl, isopentylsnolephanyl, (2-methylbutyl) sulfanyl, (1-methylbutyl) sulfanyl, neopentinolesnorephanyl, (1,2-dimethinole) Propyl) snorephanyl, (1-methylpropyl) sulfanyl, n- hexylsulfanyl, (4-methylpentyl) sulfanyl, (3
  • Examples of the “arkenyl sulfal group” include, for example, vinyl sulfal, (propen-1-yl) snorphaninole, alinoles / refaninole, isoprodinyl sulfanil, (butanol 1-1-yl) ) Sulfanyl, (Putter 2-en-l-yl) Snorrefaninole, (Butter 3-en-l-l-inole) Snolefanil, (2-methylprop-2-en-l-l) Sulfanyl, (1-methyl) Proper 2-1 1-Inore) Sulfaninore, (Penter 1-1-1 Inore) Sulfa-l, (Center 2-1 _ 1-Innole) Snorre Faninole, (Penter 3-1 1-1 Inore) Snorre Faninole, (Penter) 4-en 1-innole) Snolefaninole, (3-methinobuter 2 -en 1-yl
  • alkynyl-sulfanyl group examples include, for example, ethynylsulfanyl, (prop-l-l-in-l-yl) -snorefal, (prop-l-in-l-l-inole) -sno-lephanyl, ( Pork _ 1 in 1 _ 1 1 ⁇ nore) Sunorefaninore, (butter 3-1-1-yl) sulfal,.
  • cycloalkyl-sulfanyl group examples include, for example, cyclopropylsulfaninole, butinolesnorephanyl, cyclopentinolesnofaninole, cyclopentinolesnofaninole, cyclohexylsnorephanyl, cycloheptinolesulfanole include cycloalkyl ⁇ Ruki Ruth Alpha sulfonyl group C 3 -C 8, such as cyclopropyl O Chi pulse Honoré pyrimidin Honoré.
  • cycloalkyl-alkyl-sulfanyl group examples include, for example, (cyclopropylmethyl) sulfanyl, (1-cyclopropylethyl) sulfanyl, (2-cyclopropynoleethynole) sulfanyl, (3-cyclopropynolepropyl) sulfanyl Nil, (4-cyclopropylbutyl) sulfanyl, (5-cyclopropylpentyl) sulfanyl, (6-cyclopropylhexyl) sulfaninole, (cyclobutynolemethinole) snorphanyl, (cyclopentylmethyl) sulfaninole, (cyclobutylmethynole) -(Cyclopentylmethinole) sulfaninole, (cyclohexylmethyl) sulfanyl, (2-cyclohexy
  • arylusulfanyl group examples include, for example, C 6 to C 1 such as phenylsulfanyl, 1-naphthylsnolephaninole, 2-naphthylsulfanyl, anthrinolesulfaninole, phenanthrinolesulfanyl, and acenaphtyryl-sulfanyl. And an arylunolephanyl group of 4 .
  • aralkyl sulphanyl group examples include, for example, benzylsulfanyl, (1 (1-naphthylmethyl) sulfanyl, (2-naphthylmethyl) sulfanyl, (anthraceninolemethyl) sulfanyl, (phenanthrylmethyl) sulfanyl, (asenafthyl-methyl) sulfanyl, (diphenylmethyl) sulfanyl, (1-phenethyl) sulfanyl, (2 —Phenethyl) Sulfanyl, (1— (1-Naphthyl) ethynole) Sulfanyl, (1— (2-Naphtinol) ethyl) Sulfaninole,
  • halogenated alkylolesulfanyl group examples include groups in which the hydrogen atom of the “sulfanyl group” has been replaced with an “halogenated alkyl group”.
  • halogenated alkyl group examples include groups in which the hydrogen atom of the “sulfanyl group” has been replaced with an “halogenated alkyl group”.
  • 1 to 1 such as (3,3,3-trifluoropropyl) sulfanyl, (heptafluoropropyl) sulfanyl, (heptafluoroisopropyl) sulfanyl, (nonafluorobutyl) sulfanyl, (perfluorohexyl) sulfanyl, etc.
  • heterocyclic monosulfanyl group a group in which a hydrogen atom of the “sulfanyl group” has been substituted with a “heterocyclic group” can be mentioned.
  • heterocyclic ring the above “heterocyclic group” And the same groups as mentioned above.
  • heterocyclic monosulfanyl group examples include, for example, a monocyclic heteroaryl monosulfanyl group, a condensed polycyclic heteroaryl monosulfanyl group, a monocyclic non-aromatic heterocyclic monosulfanyl group, a condensed polycyclic ring And a non-aromatic heterocyclic monosulfanyl group of the formula.
  • Examples of the “fused polycyclic heteroaryl-sulfanyl group” include (benzimidazole-1-2-yl) sulfanyl, (quinoline-1-yl) sulfanyl, (quinoline-14-yl) sulfanyl and the like. Groups.
  • Examples of the “monocyclic non-aromatic heterocyclic monosulfanyl group” include groups such as (3-pyrrolidyl) sulfanyl and (4-piberidyl) sulfanyl.
  • Examples of the “condensed polycyclic non-aromatic heterocyclic monosulfanyl group” include groups such as (3-indolinyl) sulfanyl and (4-monochromanyl) sulfanyl.
  • acyl group examples include a formyl group, a dalioxyloyl group, a thioformyl group, a force / levamoyl group, a thiocarbamoyl group, a sulfamoyl group, a sulfinamoyl group, a carboxy group, a sulfo group, a phosphono group, and a compound represented by the following formula: :
  • acyl group In the definition of “acyl group” above, a group in which R al is a hydrocarbon group is referred to as a “hydrocarbon-carbonyl group” (specific examples: acetyl, propionyl, butyryl, isobutyryl, valerinole, isopalerinole, Pinot Loinore, Lauroinore, Millis Toinole, Palmi Toinole, Acryloyl, Propioloyl, Methacryloyl, Crotonyl, Isocrotoninole, Cyclohexylcanoleponyl, Cyclohexylmethinolecanoleponyl, Benzyl, 1-naphthyl groups such Fueniruasechiru), R a al Gaete port ring group in which the group "heterocyclic one carbonyl group” (example: 2-Tenoiru referred 3- furo I le, Ni
  • a group in which R al is a hydrocarbon group is referred to as a “hydrocarbon-oxy-one-pot oleponyl group” (Specific examples: methoxy / reponinole, ethoxycarbone) Honoré, full enoki Shikano repo alkenyl, benzyl Honoré oxy Kano repo two Honoré group, etc.), heterocyclic group and is based on the the R al "heterocycle - Okishi Ichiriki Ruponiru group” (examples: 3- Pirijiruokishi Group such as carbonyl).
  • a group in which R al is a hydrocarbon group is a “hydrocarbon-carboxyl-carbonyl group” (a specific example: a group such as pyruvoyl), and R al is a hetero group.
  • the group that is a ring group is referred to as a “heterocycle-fluorophenylcarbonyl group”.
  • a group in which R a1 is a hydrocarbon group is referred to as a “hydrocarbon oxy-propanol-carbonyl group” (specific examples: groups such as methoxalyl and ethoxylyl). ), A group in which R al is a heterocyclic group is referred to as a “heterocyclic oxy-carbonyl-carbonyl group”.
  • a group in which R al is a hydrocarbon group is a “hydrocarbon-sulfanyl-carbonyl group”, and a group in which R al is a heterocyclic group is a Faninole carboyl group ".
  • a group in which R a 1 is a hydrocarbon group is referred to as “hydrocarbon— O Kishi Chio Cal Poni Le group ", the group is a heterocyclic group is R al referred to as” heterocyclic one Okishi ⁇ Chiokarubo group ".
  • a group in which R al is a hydrocarbon group is a “hydrocarbon-sulfanyl-thiocarbonyl group”, and a group in which R al is a heterocyclic group is a “heterocyclic group”.
  • R al is a hydrocarbon group
  • R al is a heterocyclic group
  • heterocyclic group is a “heterocyclic group”.
  • N-hydrocarbon monofunctional rubamoyl group a group in which R al is a hydrocarbon group
  • R A group in which al is a heterocyclic group is referred to as an “N-heterocyclic monorubumoyl group”.
  • a group in which R a1 and R bl are a hydrocarbon group is referred to as “ ⁇ , ⁇ -di (hydrocarbon) one-pot rubamoyl group” (specific example: ⁇ , ⁇ -dimethylcarbamoyl, etc.), groups in which R al and R bl are heterocyclic groups are referred to as “N, N-di (heterocyclic) monocyclic rubamoyl groups”, and R al is a hydrocarbon group and R bl the heterocyclic group is a group but to "N_ charcoal hydrocarbon one N- to terrorist ring - substituted force Rubamoiru group", R a 1 and R 131 are together a connexion, together with the nitrogen atom to which they are attached
  • a group that is a cyclic amino group is referred to as a “cyclic amino-force luponyl group” (specific examples: groups such as morpholinocarbonyl).
  • a group in which R al is a hydrocarbon group is an “N-hydrocarbon-thiocarbamoyl group”, and a group in which R al is a heterocyclic group is “N— Heterocycle—thiocarbamoyl group ”.
  • a group in which R bl is a heterocyclic group is referred to as an “N, N-di (heterocycle) thiocarbamoyl group”, and a group in which Ra1 is a hydrocarbon group and R R1 is a heterocyclic group is referred to as “N —Hydrocarbon-N-heterocycle—thiocarbamoyl group ”, R al and R bl together form a cyclic amino group together with the nitrogen atom to which they are attached as“ cyclic amino-thiocarbo- R group ".
  • a group in which R al is a hydrocarbon group is “N_hydrocarbon-sulfamoyl group”, and a group in which R al is a hetero ring group is “N-hetero ring 1”. Sulfamoyl group ".
  • R al and R bl are hydrocarbon groups
  • ⁇ , ⁇ -di (hydrocarbon) -sulfamoyl groups groups in which R al and R bl are hydrocarbon groups are referred to as “ ⁇ , ⁇ -di (hydrocarbon) -sulfamoyl groups” (specific examples: ⁇ , ⁇ —A group such as dimethylsulfamoyl)
  • R al and R bl are heterocyclic groups as “N, N-di (heterocyclic) sulfamoyl groups”
  • R al is a hydrocarbon group
  • R bl is A group that is a heterocyclic group is an "N-hydrocarbon-N-heterocyclic-sulfamoyl group”
  • R a1 and R bl are taken together and are a cyclic amino group together with the nitrogen atom to which they are bonded.
  • a “cyclic amino-sulfonyl group” specifically examples: groups such
  • a group in which R al is a hydrocarbon group is an “N-hydrocarbon sulfinamoyl group”, and a group in which R al is a heterocyclic group is “N-hetero ring Sulfinamoyl group ".
  • groups in which R al and R bl are hydrocarbon groups are referred to as “ ⁇ , ⁇ -di (hydrocarbon) -sulfinamoyl group”, and ⁇ are heterocycles.
  • the group represented by “ ⁇ , ⁇ -di (heterocycle) -sulfinamoyl group” is referred to as “N—hydrocarbon-N—”, where R a1 is a hydrocarbon group and R bl is a heterocyclic group.
  • a heterocyclic monosulfinamoyl group and ⁇ together, together with the nitrogen atom to which they are attached, are a cyclic amino group are referred to as a "cyclic amino-sulfinyl group”.
  • a group in which R al is a hydrocarbon group is a “hydrocarbon-oxysulfonyl group”, and a group in which R al is a heterocyclic group is a “heterocyclic mono-oxy group”. Sulfonyl group ".
  • R al and R bl are hydrocarbon groups are referred to as “0, 0, 1-di (hydrocarbon) -monophosphono group”, R al and A group in which R bl is a heterocyclic group is a “0, 0, di (heterocyclic) monophosphono group”, and a group in which R al is a hydrocarbon group and R bl is a heterocyclic group is “o-carbonized”.
  • R al and R bl are hydrocarbon groups in which R al and R bl are hydrocarbon groups are referred to as “0, 0, 1-di (hydrocarbon) -monophosphono group”
  • R al and A group in which R bl is a heterocyclic group is a “0, 0, di (heterocyclic) monophosphono group”
  • R al is a hydrocarbon group and R bl is a heterocyclic group is “o-carbonized”.
  • a group in which R a 1 is a hydrocarbon group is referred to as a “hydrocarbon group”.
  • a monosulfonyl group ”(specific examples: groups such as methanesulfonyl and benzenesulfonyl), and a group in which R a1 is a heterocyclic group are referred to as a“ heterocyclic-sulfonyl group ”.
  • a group in which R al is a hydrocarbon group is referred to as a “hydrocarbon monosulfinyl group” (eg, a group such as methylsulfinyl and benzenesulfiel).
  • Ral is a heterocyclic group; ⁇ One group is called “heterocyclic-sulfiel group”.
  • Examples of the “hydrocarbon” in the groups represented by the above formulas ( ⁇ -1A) to ( ⁇ -21A) include the same groups as the above “hydrocarbon group”.
  • the "hydrocarbon mono-lponyl group” represented by the formula ( ⁇ -1A) includes an alkyl mono-yl carbonyl group, an alkenyl-carbonyl group, an alkyl-carbonyl group, a cycloalkyl mono-propyl group.
  • Examples of the “heterocycle” in the groups represented by the above formulas ( ⁇ -1A) to ( ⁇ -21A) include the same groups as the above “heterocyclic group”.
  • examples of the “heterocyclic monoaryl group” represented by the formula ( ⁇ -1A) include, for example, a monocyclic heteroaryl monoaryl group, a condensed polycyclic heteroaryl monoaryl group, and a monocyclic non-aryl group.
  • An aromatic heterocyclic monocarbonyl group and a condensed polycyclic non-aromatic heterocyclic monocyclic group are exemplified.
  • Examples of the “cyclic amino” in the groups represented by the above formulas ( ⁇ _10 ⁇ ) to ( ⁇ -16A) include the same groups as the above “cyclic amino group”.
  • a functional group when referred to as "optionally having a substituent", one or two of the functional groups may be located at a chemically possible position unless otherwise specified. Means that it may have more than one "substituent".
  • the type of substituent, the number of substituents, and the position of the substituent present in the functional group are not particularly limited, and two or more substituents If groups are present, they can be the same or different.
  • Examples of the "substituent" present in the functional group include a halogen atom, an oxo group, a thioxo group, a nitro group, a nitroso group, a cyano group, an isocyano group, a cyanate group, a thiocyanato group, an isocyanato group, an isothiocyanato group, and a hydroxy group.
  • Sulfanyl group carboxy group, sulfalcarponyl group, oxa mouth group, mesooxalo group, thiocarboxyl group, dithiocarboxy group, carpamoyl group, thiocarpamoyl group, sulfo group, sulfamoinole group, sulfino group, sulfinamoyl group, sulfinamoyl group Sulfonamoyl group, phosphono group, hydroxyphosphonyl group, hydrocarbon group, heterocyclic group, hydrocarbon-oxy group, heterocyclic monooxy group, hydrocarbon monosulfur group, heterocyclic monosulfur group, Acyl group, amino group, hydrazino group Hydrazono group, a di ⁇ Zeniru group, Ureido group, Chioureido group, Guanijino group, Karubamoimi Doyle based on
  • Such a cyclic group contains, as atoms (ring atoms) constituting a ring system, one or more heteroatoms selected from oxygen, sulfur, nitrogen and the like. And one or more substituents may be present on the ring.
  • the ring may be monocyclic or fused polycyclic, and may be aromatic or non-aromatic.
  • “Substituent” in the above definition of “optionally having a substituent” may be substituted by the above “substituent” at a chemically feasible position on the substituent.
  • the type of the substituent, the number of the substituents, and the position of the substituent are not particularly limited. When two or more substituents are substituted, they may be the same or different.
  • Examples of such a compound include, for example, an alkyl halide monoluponyl group (specific examples: trifluorophenol) A group such as cetyl), an alkyl-sulfonyl halide group (specific examples: a group such as trifluoromethanesulfonyl), an acyloxy group, an acyl-sulfanyl group, an N-hydrocarbon-amino group, an N, N-di (hydrocarbon ) Groups such as -amino, N-heterocyclic-amino, N-hydrocarbon-N-heterocycle-amino, acyl-amino, di (amino) amino and the like. Further, the “substitution” on the “substituent” may be repeated over plural times.
  • acyloxy group examples include a group in which a hydrogen atom of the “hydroxyl group” is replaced with the “acyl group”, for example, a formyloxy group, a glyoxyloyloxy group, a thioformyloxy group, Carbamoyloxy group, thiocarbamoyloxy group, sulfamoy / reoxy group, sulfinamoyloxy group, carboxyoxy group, sulfoxy group, phosphonooxy group, and the following formula:
  • a group in which R a2 is a hydrocarbon group is referred to as a “hydrocarbon-carbonyl-oxy group” (specific examples: a group such as acetoxy and benzoyloxy), and a group R a2 is The group that is a telocyclic group is referred to as a "heterocyclic monocarboxy group”.
  • a group in which R a2 is a hydrocarbon group is referred to as a “hydrocarbon-oxy-carboxy-l-oxy group”, and a group in which R a2 is a heterocyclic group is referred to as “ It is referred to as "heterocyclic oxy-lponinoleoxy group”.
  • a group in which R a2 is a hydrocarbon group is referred to as a “hydrocarbon-carbonyl-carbonyl-oxy group”
  • a group in which R a2 is a heterocyclic group is referred to as “ Heterocycle is referred to as "a heterocyclic group.”
  • a group in which R a2 is a hydrocarbon group is referred to as a “hydrocarbon-oxy-carboxy-carbonyl-r-oxy group”, and a group in which R a2 is a heterocyclic group. Is referred to as a "heterocycle-oxycarbonyl-pyroxycarbonyl group”.
  • a group in which R a 2 is a hydrocarbon group is referred to as a “hydrocarbon-sulfanyl-carbonyloxy group”, and a group in which R a 2 is a heterocyclic group. It is referred to as a "heterocyclic monosulfanyl monofluorophenyloxy group”.
  • a group in which R a2 is a hydrocarbon group is referred to as a “hydrocarbon-carboxyloxy group”, and a group in which R a2 is a heterocyclic group is referred to as a “heterocycle-l-thioka”.
  • Luponyl-oxy group ".
  • a group in which R a2 is a hydrocarbon group is referred to as a “hydrocarbon hydrocarbonoxycarbonyl group”, and a group in which R a2 is a heterocyclic group. It is referred to as "heterocycle-oxyciticarponyloxy group”.
  • a group in which R a2 is a hydrocarbon group is a “hydrocarbon-sulfanyl-thiocarburoxy group”, and a group in which R a2 is a heterocyclic group. It is referred to as a "heterocyclic monosulfanylthiocarboxyloxy group”.
  • R a2 is a hydrocarbon group
  • R a2 is a heterocyclic group
  • the group is referred to as "N-heterocyclic monorubumoyloxy group”.
  • R a2 and R b2 are the same or different and each represents a hydrocarbon group or a heterocyclic group, or R a2 and R 152 are taken together to form a nitrogen atom to which they are bonded. And both represent a cyclic amino group).
  • R a2 and R 3 ⁇ 42 are hydrocarbon groups
  • N, N-di (heterocyclic) Ichiriki Luba moil over O alkoxy group is a
  • R a2 is hydrocarbon group
  • R b2 to hetero the group is a Hajime Tamaki "N- hydrocarbon one N- heterocyclic Ichiriki Luba Moiruokishi group”
  • R a2 and R b2 connexion, group is a cyclic amino group together with the nitrogen atom to which they are attached Is referred to as a “cyclic amino-functional radicaloxy group”.
  • a group in which R a2 is a hydrocarbon group is referred to as an “N-hydrocarbon-thiocarbamoyloxy group”, and a group in which R a2 is a heterocyclic group.
  • One group is referred to as an “N-heterocyclic monothiocarbamoyloxy group”.
  • R a2 and R b2 are hydrocarbon groups are referred to as “N, N-di (hydrocarbon) -thiocarpamoyloxy group”, R a2 ⁇ Pi R b2 to the groups that are heterocyclic group "N, N-di (heterocyclic) Single Chio force Luba moil over O alkoxy group” is a
  • R a2 is a hydrocarbon group heterocyclic group R b 2 to the A group consisting of “N-hydrocarbon-N-heterocycle—thiol-bamoyloxy group”, R a 2 and R b 2 taken together, and a cyclic amino group together with the nitrogen atom to which they are attached.
  • a cyclic amino-thiocarbonyl monooxy group Is referred to as a “cyclic amino-thiocarbonyl monooxy group”.
  • a group in which Ra 2 is a hydrocarbon group is an “N-hydrocarbon-sulfamoyloxy group”, and a group in which Ra 2 is a heterocyclic group. Is referred to as “N-heterocyclic-sulfamoyloxy group”.
  • R a2 and R b2 are hydrocarbon groups are referred to as “ ⁇ , ⁇ -di (hydrocarbon) -sulfamoyloxy group”, and R a2 and R b2 to the groups that are heterocyclic group "N, N-di (heterocyclic) - sulfamoyl over O alkoxy group", groups R a2 is a heterocyclic group is R b2 charcoal hydrocarbon group Is an N-hydrocarbon-N-heterocyclic sulfamoyloxy group, a group in which Ra 2 and R b 2 are taken together and are a cyclic amino group together with the nitrogen atom to which they are attached.
  • a group in which R a2 is a hydrocarbon group is a “N-hydrocarbon-sulfinamoyloxy group”, and a group in which R a2 is a heterocyclic group. Is referred to as “N-heterocyclic monosulfinamoyloxy group”.
  • R a2 and R b2 are hydrocarbon groups are referred to as “ ⁇ , ⁇ -di (hydrocarbon) -sulfinamoyloxy group”, R a2 And a group in which R b2 is a heterocyclic group is an “N, N-di (heterocycle) sulfinamoyloxy group”; a group in which Ra 2 is a hydrocarbon group and R b2 is a heterocyclic group Is referred to as an “N-hydrocarbon-N-heterocycle-sulfinamoyl-oxy group”, and R a2 and R b2 are taken together to form a cyclic amino group together with the nitrogen atom to which they are bonded. Sulfiel-oxy group ".
  • a group in which R a2 is a hydrocarbon group is a “hydrocarbon-oxysulfonyloxy group”, and a group in which R a2 is a heterocyclic group is “ Heterocycle-oxysulfonylmonooxy group ".
  • a group in which R a2 is a hydrocarbon group is referred to as a “hydrocarbon-oxy-sulfier-loxy group”, and a group in which R a2 is a heterocyclic group is referred to as a “heterocyclic group”.
  • a ring-oxysulfininoleoxy group ".
  • a group R a 2 and R b 2 is a hydrocarbon group "0, ⁇ , over-di (hydrocarbon) Single Hosuhonookishi group", R a 2 and R b 2 to the hetero ring group der Ru group "O, O, temporary (heterocycle) Single phosphono one Okishi group", groups R a2 is a hydrocarbon group a and the heterocyclic group R h2 is Is referred to as "0-hydrocarbon-substituted mono-O'-heterocyclic-substituted phosphonooxy group".
  • a group in which R a2 is a hydrocarbon group is a “hydrocarbon monosulfonyloxy group”, and a group in which R a2 is a heterocyclic group is “heterocycle”.
  • Monosulfonyloxy group ".
  • a group in which R a2 is a hydrocarbon group is a “hydrocarbon-sulfinyloxy group”, and a group in which R a2 is a heterocyclic group is a “heterocyclic group”. Ring-sulfinyloxy group ".
  • Examples of the “hydrocarbon” in the groups represented by the formulas ( ⁇ -IB) to ( ⁇ -21 ⁇ ) include the same groups as the “hydrocarbon groups”.
  • the “hydrocarbon-carboxyloxy group” represented by the formula ( ⁇ _1 ⁇ ) includes an alkyl-1-carbonyloxy group, an alkenylcarbonyl-oxy group, an alkynyl-carboxyloxy group, and a cycloalkyl-1-carbonyl group.
  • Aliphatic hydrocarbons such as 2-hydroxy, cycloalkenyl, cycloalkyl, cycloalkenyl-carboxy, cycloalkyl, alkyl-carbonyl, etc .; -Ruoxy group; aralkyl-carboxy-roxy group; bridged cyclic hydrocarbon-carboxy group; spirocyclic hydrocarbon-carboxy-roxy group;
  • ⁇ -1 2 ⁇ to ( ⁇ -21B).
  • heterocycle in the groups represented by the above formulas ( ⁇ -1B) to (co-21 ⁇ ) include the same groups as the above “heterocycle”.
  • the “heterocyclic monocarbonyl group” represented by the formula ( ⁇ -1B) includes, for example, a monocyclic heteroaryl monocarbonyl group, a condensed polycyclic heteroaryl monocarbonyl group, and a monocyclic non-aromatic group.
  • Examples of the “cyclic amino” in the groups represented by the above formulas ( ⁇ -10B) to ( ⁇ — 16 ⁇ ) include the same groups as the above “cyclic amino group”.
  • acyloxy group “hydrocarbon monooxy group”, and “heterocyclic oxy group” are collectively referred to as “substituted oxy group”. Further, these “substituted oxy group” and “hydroxy group” are collectively referred to as “optionally substituted hydroxy group”.
  • diasylsulfanyl group examples include groups in which a hydrogen atom of the “sulfanyl group” has been replaced with an “asyl group”.
  • a formylsulfanyl group a dalioxyloylsnorfael group, a thioformylsulfanyl group, a canoleba Moylsulfani finamoylsnorefanyl, carboxysnorefinole, sulfosulfaenole 8 groups, phosphonosulfanyl group, and the following formula
  • R a 3 and R b3 identical or different, substituted and may hydrocarbon group, or have a substituent to good or represents a heterocyclic group, or R a 3 and R b3 are together a connexion, together with the nitrogen atom to which they are attached, optionally substituted Represents a good cyclic amino group).
  • a group in which R a3 is a hydrocarbon group is referred to as a “hydrocarbon one-pot sulfonyl sulfanyl group”, and a group in which R a3 is a heterocyclic group. It is referred to as "heterocyclic monocarbonyl-sulfanyl group”.
  • R a 3 is a hydrocarbon group a is based on the "hydrocarbon one Okishi one carbo - Rusurufa - Le group", in the heterocyclic group is R a 3 Certain groups are referred to as "heterocycle-l-oxyl-l-poryl-sulfanyl groups".
  • R a3 is a hydrocarbon group
  • R a3 is a heterocyclic group
  • the group is referred to as a "heterocyclic-carboxy-carbonyl-sulfur group”.
  • the group R a3 is a hydrocarbon group "hydrocarbon one Okishi one Kano repo Nino rate Kano repo Nino race Alpha group", terror to the R a 3
  • the group that is a ring group is referred to as a “heterocyclic monocarbonyl-carbonyl-sulfanyl group”.
  • a group in which R a3 is a hydrocarbon group is a “hydrocarbon-sulfanyl-potassium sulfonyl group”, and a group in which R a3 is a heterocyclic group. Is referred to as a “heterocycle-sulfanyl-potassium ru-sulfanyl group”.
  • R a 3 is based on the "hydrocarbon one Chiokarubo two loose Alpha group" is a hydrocarbon group, a group which is heterocyclic group is R a 3 It is referred to as "heterocyclic-l-carboxy-l-sulfanyl group".
  • a group in which R a3 is a hydrocarbon group is referred to as a “hydrocarbon monooxycarbocarbonylsulfanyl group”, and a group in which R a3 is a heterocyclic group.
  • the group is referred to as a "heterocycle-l-oxyl-l-phenyl-sulfanyl group”.
  • a group in which Ra 3 is a hydrocarbon group is referred to as a “hydrocarbon-1-sulfanyl-thiopropyl-sulfanyl group”, and a group in which Ra 3 is a heterocyclic group.
  • One group is referred to as "heterocycle-snolephanyl-thiocarbodilsulfanyl group”.
  • a group in which Ra3 is a hydrocarbon group is referred to as "N-hydrocarbon”.
  • a group in which Ra3 is a heterocyclic group is referred to as an "N-heterocyclic rubamoyl-sulfanyl group”.
  • R a3 and R b3 are hydrocarbon groups are referred to as “ ⁇ , ⁇ -di (hydrocarbon) mono-lupamoyl-sulfanyl group”, R a Groups in which 3 and R b 3 are heterocyclic groups are referred to as “N, N-di (heterocycle) —hydrorubamoyl-sulfanyl groups”, Ra 3 is a hydrocarbon group, and R b3 is a heterocyclic group.
  • a group is defined as an “N-hydrocarbon-N-heterocyclic one-membered rubamoyl-sulfanyl group”, a group in which Ra3 and Rb3 are taken together and are a cyclic amino group together with the nitrogen atom to which they are attached. It is referred to as “cyclic amino-carbonyl-sulfamoinole group”.
  • the group R a3 is a hydrocarbon group "N- hydrocarbons over Chio Scarpa Moi Ruth Alpha group" is a heterocyclic group R a3 is the group Is referred to as an "N-heterocyclic monothiocarbamoyl-sulfanyl group".
  • R a3 and R b3 are hydrocarbon groups are referred to as “ ⁇ , ⁇ -di (hydrocarbon) monothiocarbamoyl-sulfanyl group”, ⁇ and A group in which ⁇ is a heterocyclic group is referred to as a “ ⁇ , ⁇ -di (heterocyclic) monothiocarbamoyl-sulfanyl group”, and a group in which R a3 is a hydrocarbon group and R b3 is a heterocyclic group.
  • N-hydrocarbon-N-heterocyclic-thiocarbamoyl-sulfanyl group a group in which Ra 3 and R b 3 together form a cyclic amino group together with the nitrogen atom to which they are bonded, It is referred to as "Norchio force 'norebonylsulfanyl group'.”
  • R a3 is a hydrocarbon group a is based on the "N- hydrocarbons over sulfamoylcarbamoyl Ruth Alpha group", the group is a heterocyclic group R a3 is the "N_ Heterocyclic monosulfamoyl-sulfanyl group ".
  • the group R a3 and R b3 are hydrocarbon groups "N, N-di (hydrocarbon) over sulfamoylcarbamoyl Ruth Alpha group", 1 33 and 1 ⁇
  • a group in which 3 is a heterocyclic group is referred to as an “N, N-di (heterocycle) -sulfamoyl-sulfinyl group”
  • a group in which R a3 is a hydrocarbon group and R b3 is a heterocyclic group is referred to as “N —Hydrocarbon—N-heterocyclic sulfamoyl-sulfur group ”
  • R a3 and R b3 are taken together to form
  • a group which is a cyclic amino group together with the nitrogen atom to which it is bonded is referred to as a “cyclic amino-sulfonyl sulfansyl group”.
  • R a 3 is a hydrocarbon group "N- hydrocarbon one sulphates Inamo Lee Ruth Alpha group", the R a3 is The group is referred to as "N-heterocycle-sulfinamoyl-sulfanyl group”.
  • R a3 and R b3 are hydrocarbon groups are referred to as “ ⁇ , ⁇ -di (hydrocarbon) -sulfinamoyl-sulfanyl group”, R a3 ⁇ Pi R 3 ⁇ 43 to take group is heterocyclic group "N, N-di (heterocyclic) Single sulphates Inamo Lee Ruth Alpha - Le group", R a 3 is a hydrocarbon radical R b 3 hetero into rings The group is an “N-hydrocarbon-N-heterocycle-sulfinamoyl-sulfanyl group”, and R a 3 and R 3 ⁇ 4 3 together form a cyclic amino group together with the nitrogen atom to which they are bonded. Is referred to as a “cyclic aminosulfur-sulfanyl group”.
  • the group R a 3 is a hydrocarbon group "hydrocarbon - O Kishi sulfonyl Ruth Alpha group", the group is a heterocyclic group R a3 is the ""Heterocyclic mono-oxysulfonyl-sulfanyl group”.
  • R a 3 is based on a hydrocarbon group "hydrocarbon - Okishisurufi two loose Alpha group", the group is a heterocyclic group R a3 is to the ""Terocyclic-oxysulfinyl-sulfanylgroup".
  • R a 3 and R b 3 are hydrocarbon groups are defined as “0, ⁇ , di (hydrocarbon) monophosphonose ruphanyl group”, and R A group in which a3 and Rb3 are heterocyclic groups is referred to as an "O, 0, one di (heterocycle) one phosphonose ruphanyl group", and a group in which Ra3 is a hydrocarbon group and Rb3 is a heterocyclic group. It is referred to as "0-hydrocarbon-0,1-heterocyclic-monophosphonosulfanyl group".
  • R a 3 is a hydrocarbon group a is based on the "hydrocarbon one sulfonyl Ruth Alpha group", "heteroaryl groups are heterocyclic group R a3 is the Ring-norehonyl-sulfanyl group ".
  • a group in which R a3 is a hydrocarbon group is referred to as a “hydrocarbon group”.
  • a group in which R a 3 is a heterocyclic group is referred to as a “heterocyclic monosulfanyl group”.
  • hydrocarbon-potassium sulfanyl group represented by the formula ( ⁇ -1 C) includes an alkyl-carbonyl-sulfanyl group, an alkenylcanoleponyl-sulfanyl group, an anoreckini, a lucanoleponyl-sulfanyl group Groups, cycloalkanols, phenols, cycloalkenes, cycloalkanes, cycloalkanes, cycloalkanes, cycloalkanes, cycloalkanes, cycloalkanols, cycloalkanols, alkynoles, canolepinolaces Aliphatic hydrocarbons such as fanyl groups, monocyclic sulfon
  • Examples of the “heterocycle” in the groups represented by the above formulas (c-1C) to ( ⁇ -21C) include the same groups as the above “heterocyclic group”.
  • the “heterocyclic monocarboryl sulfanyl group” represented by the formula ( ⁇ -1 C) for example, a monocyclic heteroaryl monoaryl sulfanyl group, a condensed polycyclic heteroaryl monoaryl sulfo group
  • Examples include a bi-sulfanyl group, a monocyclic non-aromatic heterocyclic ring-caprolucylsulfanyl group, and a condensed polycyclic non-aromatic heterocyclic ring-carboylsulfuryl group.
  • Examples of the “cyclic amino” in the groups represented by the above formulas ( ⁇ -10C) to ( ⁇ -16C) include the same groups as the above “cyclic amino group”.
  • acyl-sulfanyl group “hydrocarbon-sulfanyl group” and “heterocycle-sulfanyl group” are collectively referred to as “substituted sulfanyl group”. Further, these “substituted sulfanyl groups” and “sulfanyl groups” are collectively referred to as “optionally substituted sulfanyl groups”. ' Examples of the “N-hydrocarbon-amino group” include groups in which one hydrogen atom of the “amino group” has been substituted with a “hydrocarbon group”.
  • ⁇ -alkyl-amino group examples include a ruamino group, a -alkynyl-amino group, a -cycloalkyl-amino group, a -cycloalkyl-alkyl-amino group, a -aryluamino group, a -aralkylamino group and the like.
  • ⁇ -alkylamino group examples include, for example, methylamino, ethylamino, ⁇ -propylamino, isopropylamino, ⁇ -butylamino, isobutylamino, sec-butynoleamino, tert-butylamino, n-pentylamino, isopentylamino, (2-methylbutyl) Amino, (1-methylbutyl) amino, neopentylamino, (1,2-dimethylpropyl) amino, (1-ethylpropyl) amino, n-hexylamino, (4-methylpentyl) amino, (3-methylpentyl) Amino, (2-methylpentyl) amino, (1-methylpentyl) amino, (3,3-dimethylbutyl) amino, (2,2-dimethylbutyl) amino, (1,1-dimethylbutyl) amino, (1 , 2-Di
  • N-alkenylamino group examples include, for example, bieramino, (propene-111-amino), arylamino, isopropenylamino, (butene-1-yl) amino, Amino (buta 2-en-l-yl) Amino (butter 3-en-l-yl) Amino, (2-methylprop-2-en-l-yl) Amino, (1-methyl-propane 2-yl) Amino, (Penter 1-11) Amino, (Penter 2-11) Amino, (Penter 3-11) Amino, (Penter 3-11) Penter 4-1-1-1 Amino, 3-Methylbut-2-1- 1-yl) Amino, (3-Methylbuta-3-1-1-yl) Amino, (Hexa1-1-1-1-1 f) Amino, (Hex-1-2-1-1-1) Amino, (Hexa 1 _ 3 _ 1 _ 1)
  • N-alkynyl-amino group examples include, for example, ethuramino, (prop-1-in-1-yl) amino, (prop-1--2--1-yl) amino, (but-1-in-1) —Yl) Amino, (Butter 3—in 1_yl) Amino, (1—Methylpropane 2—in 1—yl) Amino, (Penter 1—in 1—yl) Amino,
  • N- cycloalkyl one Amino group for example, cyclopropyl ⁇ Mino, cyclobutylcarbamoyl Honoré amino, consequent opening pentylamino, Puchiruamino to consequent opening Kishinoreamino, the consequent opening, C 3 -C such cycloalkyl O lipped Rua Mino 8 N-cycloalkyl monoamino groups.
  • N-cycloalkyl-alkyl-amino group examples include (cyclopropylmethyl) amino, (1-cyclopropylethyl) amino, (2-cyclopropylethyl) amino, and (3-cyclopropylpropyl) amino.
  • N- Ariruamino group includes, for example, Fueniruamino, 1-naphthyl Amino, 2 one Nafuchiruamino, anthryl amino, full Henin tolyl ⁇ amino, such as ⁇ Se naphthylene Leni Rua amino C 6 -C 1 4 of N- mono- c the Ariruamino group
  • N-aralkylamino examples include, for example, penzinoleamino, (1-naphthylmethyl) amino, (2-naphthylmethyl) amino, (anthracenylmethyl) amino, and (phenanthrenylmethyl) Amino, (acenaphthylenylmethyl) Amino,
  • C 7 -C i 6 N-aralkyl monoamino groups such as (1-naphthyl) hexyl) amino and (6- (2-naphthyl) hexyl) amino.
  • N, N-di (hydrocarbon) amino group examples include groups substituted by two hydrogen atoms “hydrocarbon group” of “amino group”.
  • Examples of the “ ⁇ -heterocyclic-amino group” include a group in which one hydrogen atom of the “amino group” is substituted with a “heterocyclic group”.
  • a “heterocyclic group” For example, (3-pyrrolidinyl) amino, (4-pibelidi -Le) Amino, (2-tetrahydrodrobilanyl) amino, (3-indolinyl) amino, (4-chromanyl) amino, (3-chenyl) amino, (3-pyridyl) amino, (3-quinolyl) amino, (3-quinolinyl) amino 5—Indolyl) groups such as amino.
  • Examples of the “ ⁇ -hydrocarbon mono-heterocyclic amino group” include a group in which two hydrogen atoms of the “amino group” are substituted one by one with the “hydrocarbon group” and the “heterocyclic group”, For example, ⁇ -methyl- ⁇ - (4-piperidinyl) amino, ⁇ - (4-chromanyl) - ⁇ -methylamino, ⁇ -methyl- ⁇ - (3-chenyl) amino, ⁇ -methyl- And N- (3-pyridyl) amino, N-methyl-N- (3-quinolyl) amino and the like.
  • acyl-amino group examples include a group in which one hydrogen atom of the “amino group” is substituted with an “acyl group”.
  • examples thereof include a formylamino group, a glyoxyloylamino group, a thioformylamino group, Rubamoylamino group, thiocarbamoylamino group, sulfamoylamino group, sulfinamoylamino group, lipoxyamino group, sulfoamino group, phosphonoamino group, and the following formula:
  • R a4 and R b4 are the same or different and each represent a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent, or a4 and become R b4 gar cord, together with their nitrogen atom to which they are bonded, a group represented by the representative) a good cyclic amino group which may have a substituent.
  • acyl-amino group In the definition of "acyl-amino group",
  • a group in which R a4 is a hydrocarbon group is referred to as a “hydrocarbon one-pot amino group”, and a group in which R a4 is a heterocyclic group is referred to as a “heterocyclic group”. It is referred to as "one-strength ponyl-amino group.”
  • a group in which R a4 is a hydrocarbon group is referred to as a “hydrocarbon-oxy-carboxy-amino group”, and a group in which R a4 is a heterocyclic group is referred to as a “heterocyclic group”. It is referred to as an "oxyl-propyl amino group”.
  • a group in which R a4 is a hydrocarbon group is referred to as a “hydrocarbon-carboxy-loop amino group”, and a group in which R a4 is a heterocyclic group is referred to as “heterocycle”. Ring "Carboyl-Ru-Polyamino group”.
  • a group in which R a4 is a hydrocarbon group is a “hydrocarbon-oxy-oxyl-l-ponyl-carboxy-l-amino group”, and a group in which R a4 is a heterocyclic group. Is referred to as a "heterocyclic mono-functional amino group”.
  • a group in which R a4 is a hydrocarbon group is referred to as a “hydrocarbon-sulfanyl-propanol group”, and a group in which R a4 is a heterocyclic group is referred to as a “heterocyclic group”.
  • Ring-snorefanyl-canoleponinole amino group ".
  • a group in which R a4 is a hydrocarbon group is referred to as a “hydrocarbon-thiocarborylamino group”, and a group in which R a4 is a heterocyclic group is referred to as a “heterocyclic-carboxy group”. This is referred to as a "2-amino group.”
  • a group in which R a4 is a hydrocarbon group is referred to as a “hydrocarbon-hydroxy-carbo-luamino group”, and a group in which R a4 is a heterocyclic group is referred to as a “heterocyclic group”. Ring ".
  • a group in which R a4 is a hydrocarbon group is referred to as a “hydrocarbon-1-sulfanyl-thiocarbinylamino group”, and a group in which R a4 is a heterocyclic group is referred to as “ Heterocycle-sulfanyl-thiocarbo-l-amino group ".
  • R a 4 is a hydrocarbon group a is based on the "N- hydrocarbon Motoichi force Rubamoiru group", the group is a heterocyclic group R a4 is the " N—heterocycle—carbamo "Ylamino group”.
  • the group R a4 ⁇ Pi 1 ⁇ 4 is a hydrocarbon group ", N- di (hydrocarbon) Ichiriki Luba carbamoyloxy over amino group"
  • R a 4 is heterocyclic group
  • R a4 is a hydrocarbon group to the R b4
  • the group is referred to as an “N-hydrocarbon-N-heterocyclic monovalent rubamoyl-amino group”
  • a group that is a cyclic amino group together with the nitrogen atom to which R a4 and R b4 are linked together is referred to as “ Cyclic amino-carbo-amino group ".
  • a group in which R a4 is a hydrocarbon group is referred to as an “N-hydrocarbon-thiocarbamoyl-amino group”, and a group in which R a4 is a heterocyclic group is referred to as “ N-heterocyclic monothiocarbamoyl-amino group ".
  • the group R a4 and R b4 are hydrocarbon groups " ⁇ , ⁇ - di (hydrocarbon) Single Chio carbamoylamino over amino group", R a 4 ⁇ Pi
  • R b 4 is a heterocyclic group
  • Ra 4 is a hydrocarbon group
  • R b 4 is a heterocyclic group
  • N-hydrocarbon_N-heterocycle—thiol-bamoyl-amino group is a group in which R a4 and R b4 together form a cyclic amino group together with the nitrogen atom to which they are attached. It is called "cyclic amino-thiocarbonyl-amino group”.
  • a group in which R a4 is a hydrocarbon group is “N-hydrocarbon-sulfamoyl-amino group”, and a group in which R a4 is a heterocyclic group is “N— Heterocyclic monosulfamoyl-amino group ".
  • R a4 and R b4 are hydrocarbon groups are referred to as “di (hydrocarbon) sulfamoyl-amino groups”, and R a4 and length 134 are hetero groups.
  • the group that is a ring group is an “N, N-di (heterocycle) sulfamoyl-amino group”, and the group that R a4 is a hydrocarbon group and Rb4 is a heterocyclic group is “N-hydrocarbon-N-”.
  • R a4 is based on "N- hydrocarbon one sulphates Inamo yl chromatography amino group” is a hydrocarbon group, a group which is heterocyclic group R a4 is It is referred to as "N-heterocyclic monosulfinamoyl-amino group".
  • R a4 ⁇ Pi R b4 is a group that is a hydrocarbon group "N, N-di (hydrocarbon) Suru Fuinamoiru one Amino group", R a4 And the group in which 4 is a heterocyclic group is referred to as “N, N-di
  • a group in which R a4 is a hydrocarbon group is a “hydrocarbon—oxysulfonyl-amino group”, and a group in which R a4 is a heterocyclic group is a “hetero group”. This is referred to as a “cyclic oxenolephoninole amino group”.
  • a group in which R a4 is a hydrocarbon group is a “hydrocarbon-oxysulfinyl-1-amino group”, and a group in which R a4 is a heterocyclic group. Is referred to as "heterocyclic oxysulfenyl monoamino group”.
  • a group in which R a4 is a hydrocarbon group is a “hydrocarbon monosulfonylamino group”, and a group in which R a4 is a heterocyclic group is “heterocyclic one”. Sulfonylamino group ".
  • a group in which R a4 is a hydrocarbon group is referred to as a “hydrocarbon-sulfyl-amino group”, and a group in which R a4 is a heterocyclic group is referred to as “ Heterocyclic monosulfinyl monoamino group ".
  • hydrocarbon in the group represented by the above formulas ( ⁇ -1D) to (co_21D) And the same groups as the above "hydrocarbon group”.
  • the “hydrocarbon mono-amino group” represented by the formula ( ⁇ -1D) includes an alkyl mono-amino group, an alkenylcarbonyl-amino group, an alkynyl-carbonyl amino group, Aliphatic hydrocarbons such as cycloalkyl-carboxy-amino groups, cycloalkenyl-carboxy-amino groups, cycloalkenyl-amino acids, cycloalkenyl-alkyl-amino groups, etc.
  • heterocycle in the groups represented by the above formulas ( ⁇ -1D) to (C0-21D) include the same groups as the above “heterocycle”.
  • the “heterocyclic monophenylamino group” represented by the formula ( ⁇ -1D) includes, for example, a monocyclic heteroaryl monoaryl group, a fused polycyclic heteroaryl group. And a monocyclic non-aromatic heterocyclic monocyclic amino group and a condensed polycyclic non-aromatic heterocyclic monocarboxyamino group.
  • Examples of the “cyclic amino” in the groups represented by the above formulas ( ⁇ -10D) to (co-16D) include the same groups as the above “cyclic amino group”.
  • di (acyl) amino group two hydrogen atoms of the “amino group” are substituted with the “acyl group” in the definition of the “substituent” in the above “optionally having a substituent”.
  • examples thereof include di (formyl) -amino group, di (dalioxyloyl) -amino group, di (thioformyl) -amino group, di (carbamoyl) -amino group, di (thiolbamoyl) -amino group, and di (sulfamoyl) group.
  • ⁇ and ⁇ are the same or different and represent a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent, Alternatively R a 5 ⁇ Pi R b 5 are taken together with their nitrogen atom to which they are attached a group represented by represents) an optionally cyclic amino group which may have a substituent and the like
  • a group in which Ra5 is a hydrocarbon group is referred to as "bis (hydrocarbon group)
  • a group in which R a5 is a heterocyclic group is referred to as a “bis (heterocyclic monocarbonyl) -amino group”.
  • a group in which R a5 is a hydrocarbon group is referred to as a “bis (hydrocarbon-oxy-bonyl) -amino group”, and a group in which R a5 is a heterocyclic group. It is referred to as "bis (heterocycle-l-oxyl-l-ponyl) -amino group”.
  • a group in which R a5 is a hydrocarbon group is a “bis (hydrocarbon-carbonyl-carbonyl) -amino group”, and a group in which R a5 is a heterocyclic group is “bis (hetero group)”. Ring-Carbonyl-Luponyl) -Amino Group ".
  • a group in which R a5 is a hydrocarbon group is a “bis (hydrocarbon-l-oxy-carboxycarbonyl) amino group”, and a group in which R a5 is a heterocyclic group. Is referred to as a “bis (heterocyclic oxy-l-onyl-l-onyl) -amino group”.
  • a group in which R a5 is a hydrocarbon group is a “bis (hydrocarbon-sulfanyl-carbonyl) -amino group”
  • a group in which R a5 is a heterocyclic group is “ Bis (heterocyclic monosulfanyl-carbonyl) -amino group ".
  • a group in which R a5 is a hydrocarbon group is a “bis (hydrocarbon—thiocarbol) —amino group”, and a group in which R a5 is a heterocyclic group. It is called "bis (heterocyclic-thiocarbonyl) -amino group”.
  • a group in which R a5 is a hydrocarbon group is referred to as a “bis (hydrocarbon monooxycarbonyl) -amino group”, and a group in which R a5 is a heterocyclic group is referred to as “bis ( Heterocyclic monooxycarbyl) monoamino group ".
  • a group in which R a5 is a hydrocarbon group is a “bis (hydrocarbon-sulfanyl-thiocarbonyl) -amino group”, and a group in which R a5 is a heterocyclic group.
  • R a 5 is a group that is a hydrocarbon radical "bis (N- hydrocarbon Ichiriki Rubamoiru) Amino group", the group is a heterocyclic group is R a 5 It is referred to as “bis (N-heterocycle-lubamoyl) -amino group”.
  • a group in which R a5 and R 3 ⁇ 45 are hydrocarbon groups is referred to as a “bis [N, N-di (hydrocarbon) monorubumoyl] -amino group ”, and the group in which ⁇ and ⁇ are heterocyclic groups are referred to as“ bis [N, N-di (heterocycle) monorubumoyl]] — "Amino group”
  • a group in which R a5 is a hydrocarbon group and R b5 is a heterocyclic group is referred to as “bis (N-hydrocarbon_N-one-heterocyclic-single-rubamoyl) -amino group”
  • R a5 and R b5 together
  • the group that is a cyclic amino group together with the nitrogen atom to which they are attached is called a "bis (cyclic amino-carbonyl) monoamino group”.
  • a group in which R a5 is a hydrocarbon group is a “bis (N-hydrocarbon monothiocarbamoyl) -amino group”, and R a5 is a heterocyclic group.
  • a group in which R a5 is a hydrocarbon group and R b5 is a heterocyclic group is a “bis (N—hydrocarbon—N—heterocyclic monothiocarbamoyl) —amino group”, and R a5 and R b5 are Together, the group that is a cyclic amino group, together with the nitrogen atom to which they are attached, is referred to as a "bis (cyclic amino-thiocarbonyl) -amino group.”
  • a group in which R a5 is a hydrocarbon group is a “bis (N-hydrocarbon-sulfamoyl) amino group”
  • a group in which R a5 is a heterocyclic group is “ Bis (N-heterocycle-l-sulfamoyl) -amino group ".
  • a group in which R a5 and R b5 are hydrocarbon groups is a “bis [N, N-di (hydrocarbon) -sulfamoyl] -amino group”, and R a5 and R b5 are A group that is a telocyclic group is referred to as “bis [N, N-di (heterocycle) -sulfamoyl] -amino group”, and a group in which Ra5 is a hydrocarbon group and Rb5 is a heterocyclic group is referred to as “bis ( N- hydrocarbons one N- heterocyclic - sulfamoyl) - amino group ", R a 5 ⁇ Pi R b 5 are together a connexion, based on" bis cyclic amino group together with the nitrogen atom to which they are attached (Cyclic amino-sulfonyl) monoamino group ".
  • heterocyclic group is a group of "bis [N, N-di (heterocyclic) Single Surufuinamoiru] one Amino group", the group R a5 is a heterocyclic group and is to have R b5 hydrocarbon group " bis (N- hydrocarbon one N- heterocyclic - Surufuinamoiru) amino group ", become R a5 and R b5 gar cord," bi scan a group is a cyclic amino group together with the nitrogen atom to which they are attached (Cyclic amino-sulfinyl) monoamino group ".
  • a group in which R a5 is a hydrocarbon group is a “bis (hydrocarbon-oxysulfonyl) amino group”, and a group in which R a5 is a heterocyclic group. It is called "bis (heterocycle-oxysulfonyl) -amino group”.
  • a group in which R a5 is a hydrocarbon group is a “bis (hydrogenoxyoxysulfinyl) -amino group”
  • a group in which R a5 is a heterocyclic group is “ Bis (heterocyclic-oxo-sulfiel) -amino group ".
  • R a5 and R b5 are hydrocarbon groups are referred to as “bis [O, O′—di (hydrocarbon) monophosphono] —amino groups” and R a5 A group in which R b5 is a heterocyclic group; a group in which R a5 is a hydrocarbon group and R b5 is a heterocyclic group; “bis [0, O′—di (heterocycle) -monophosphono] amino group”; Is referred to as a “bis ( ⁇ one hydrocarbon—0, one heterocycle, one phosphono) monoamino group”.
  • a group in which R a5 is a hydrocarbon group is a “bis (hydrocarbon-sulfonyl) -amino group”, and a group in which R a5 is a heterocyclic group is “bis”. (Heterocycle-sulfonyl) monoamino group ".
  • a group in which R a5 is a hydrocarbon group is a “bis (hydrocarbon-sulfiel) monoamino group”
  • a group in which R a5 is a heterocyclic group is “bis ( Heterocyclic monosulfinyl) -amino group ".
  • the “bis (hydrocarbon monocarbonyl) amino group” represented by the formula (co-l E) includes a bis (alkylcarbonyl) amino group, a bis (alkenylcarbonyl) amino group, and a bis (alkylcarbonyl) amino group.
  • Nyl-carbonyl) -amino group bis (cycloalkyl-carbonyl) -amino group, bis (cycloalkenylcarbonyl) -amino group, bis (cycloalkenyl-carbonyl) monoamino group, bis (cycloalkyl-alkyl-carboyl) -amino Bis (aliphatic hydrocarbon monocarbonyl) -amino group; bis (aryl monocarbonyl) monoamino group; bis (aralkyl-carbonyl) monoamino group; bis (bridged cyclic hydrocarbon monopropyl) -amino group A bis (spirocyclic hydrocarbon monopropionyl) monoamino group; Include (terpene hydrocarbon one carbonyl) Amino group.
  • the “heterocycle” in the groups represented by the above formulas (1-1E) to ( ⁇ -21E) include the same groups as the above “heterocycle”.
  • the “bis (heterocyclic monocarbonyl) amino group” represented by the formula ( ⁇ -1E) includes, for example, a bis (monocyclic heteroaryl monocarbonyl) amino group and a bis (condensed polycyclic heterocarbonyl) amino group. And a bis (monocyclic non-aromatic heterocyclic monocyclic phenyl) amino group and a bis (condensed polycyclic non-aromatic heterocyclic-carbonyl) amino group.
  • acyl-amino group and “di (acyl) amino group” are collectively referred to as “acyl-substituted amino group”.
  • N-hydrocarbon-amino group N, N-di (hydrocarbon) -amino group
  • N-heterocyclic-amino group N-hydrocarbon-1-N-heterocyclic ring—
  • amino group cyclic amino group
  • acyl-amino group and “di (acyl) -amino group” are collectively referred to as “substituted amino group”.
  • A can be a hydrogen atom or an acetyl group, and is preferably a hydrogen atom.
  • ring Z a group represented by “formula O—A (where A is as defined above) and formula —CO NH-E (where E is as defined above)
  • ⁇ arene '' of the ⁇ arene which may further have a substituent '' include a monocyclic or condensed polycyclic aromatic hydrocarbon, for example, a benzene ring, a naphthalene ring, an anthracene ring, Examples include a phenanthrene ring and an acenaphthylene ring.
  • a Aren of benzene ring, c 6 to c 1 0, such as a naphthalene ring, more preferably a benzene ring and a naphthalene ring, most preferably a benzene ring.
  • ring Z a group represented by “formula O—A (where A is as defined above) and formula —CO NH—E (wherein E is as defined above) Is an optionally substituted arene ”S (Formula 1 O—A (where A is as defined above) and Formula 1CO NH—E (wherein E Is the same as defined above), a benzene ring which may further have a substituent in addition to the group represented by the formula: And a benzene ring having one to three further substituents in addition to the group represented by the formula: CO NH—E (where E is as defined above).
  • a group represented by the formula: O—A (wherein A has the same meaning as defined above) and the formula—CONH—E (wherein E has the same meaning as defined above) Has one more substituent in addition to Benzene ring ".
  • the substituent is preferably a group selected from the following “substituent group ⁇ -lz”, and more preferably a halogen atom and a tert-butyl group [(1,1-dimethyl) Jet And most preferably a halogen atom.
  • R z is preferably a group selected from the following “substituent group ⁇ - 2”, more preferably a halogen atom and a tert-butyl group, most preferably a halogen atom It is.
  • a group represented by “Formula — 0—A (where A is as defined above) and Formula—CO NH—E (where E is as defined above) Is an optionally substituted arene ”S (Formula 10—A (where A is as defined above) and Formula 1 CO NH—E (where E is In the case of a "naphthalene ring which may further have a substituent in addition to the group represented by the above definition)", a naphthalene ring is preferable.
  • ring Z a group represented by “Formula _ 0 _ A (where A is as defined above) and Formula —CO NH—E (where E is as defined above)
  • the “heteroarene” of the “heteroarene that may further have a substituent” further includes a heteroatom selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like as an atom (ring atom) constituting a ring system.
  • Monocyclic or condensed polycyclic aromatic heterocycles containing at least one atom of 1 to 3 atoms include, for example, a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isooxazole ring, a thiazole ring, and an isothiazole.
  • No. it is a 5- to 10-membered monocyclic or condensed polycyclic aromatic heterocycle, and more preferably, a thiophene ring, a pyridine ring, an indole ring, and a quinoxaline ring.
  • ring ⁇ a group represented by “Formula 1 ⁇ — ⁇ (where A is as defined above) and Formula 1 CO NH—E (where E is as defined above)
  • the “substituent” of the “heteroarene optionally having a substituent” includes the same group as the “substituent” in the above definition of “optionally having a substituent”. No.
  • the position of the substituent on the heteroarene is not particularly limited. When two or more substituents are present, they may be the same or different.
  • ring Z a group represented by “formula O—A (where A is as defined above) and formula —CO NH—E (wherein E is as defined above)
  • the “substituent” of the “heteroarene which may further have a substituent” in addition to the above is preferably a halogen atom.
  • Examples of the “substituent” of the “2,5-disubstituted phenyl group” in the definition of E include the same groups as the “substituent” in the above definition of “may have a substituent”.
  • Specific examples of suitable groups of “2,5-disubstituted phenyl group” in the definition of E include the groups shown in the following “substituent group ⁇ -le”.
  • 2-chloro-5-nitrophenole group 2-methoxy-5- (phenylcanolebamoyl) phenyl group, 5-acetylamino-2-methoxyphenyl group, 5-methoxy-2-methylphenyl group, 2,5 —Dibutoxyphenyl group, 2,5-diisopen Tinoleoxy group, 5-carpamoinole_2-methoxyphenyl group, 5-[(1,1-dimethyl) propynole] 1-2-phenoxyphenyl group, 2-hexyloxy_5-methanesulfonyl group, 5_ [ (2,2-dimethyl) propionyl] 12-methylphenyl, 5-methoxy2_ (1_pyrrolyl) phenyl, 5-chloro-2 -_ (p-toluenesulfonyl) phenyl, 2-chloro-5- ( p-toluenesulfonyl) phenyl group, 2-fluoro-5
  • Examples of the “substituent” of the “3,5-disubstituted phenyl group” in the definition of E include the same groups as the “substituent” in the above definition of “may have a substituent”.
  • Specific examples of suitable groups of the "3,5-disubstituted phenyl group” in the definition of E include the groups shown in the following "substituent group ⁇ -3e".
  • the “3,5-disubstituted phenyl group” in the definition of E above is a “3,5-disubstituted phenyl group (provided that at least one of the substituents is a trifluoromethyl group. )), And more preferably, a group selected from the following “substituent group ⁇ _4e”. Most preferably, 3,5-bis (trifluoromethyl) phenyl Group.
  • a monocyclic or condensed polycyclic heteroaryl group which may have a substituent (provided that the heteroaryl group is (1) a ring directly connected to one CO NH— group in the formula (I)) Is a fused polycyclic heteroaryl group in which is a benzene ring, (2) an unsubstituted thiazol-2-yl group, and (3) an unsubstituted benzothiazol-2-yl group). Is the same group as the “substituent” in the definition of “may have a substituent”.
  • the position of the substituent on the heteroaryl group is not particularly limited. When two or more substituents are present, they may be the same or different.
  • the “monocyclic heteroaryl group” of the “monocyclic or condensed polycyclic heteroaryl group optionally having substituent (s)” in the definition of E above includes the “monocyclic heteroaryl group” in the definition of the above “heterocyclic group”. And the same groups as the “cyclic heteroaryl group”.
  • the “monocyclic or condensed polycyclic heteroaryl group optionally having substituent (s)” in the definition of E above includes: (1) a ring directly connected to one CONH— group in the general formula (I) is a benzene ring; Excludes certain fused polycyclic heteroaryl groups, (2) unsubstituted thiazol-2-yl groups, and (3) unsubstituted benzothiazol-2-yl groups.
  • ⁇ monocyclic or condensed polycyclic heteroaryl group '' of the ⁇ monocyclic or condensed polycyclic heteroaryl group which may have a substituent '' in the definition of E, preferably 5 to A 10-membered monocyclic or fused polycyclic heteroaryl group
  • suitable groups include a thiazolyl group, a thienyl group, a pyrazolyl group, an oxazolyl group, a 1,3,4-thiadiazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazuryl group, and a quinolyl group.
  • ⁇ monocyclic or condensed polycyclic heteroaryl group '' of the ⁇ monocyclic or condensed polycyclic heteroaryl group which may have a substituent '' in the definition of E above, more preferably 5 And more preferably a thiazolyl group, a chenyl group, a pyrazolyl group, an oxazolyl group, and a 1,3,4-thiadiazolyl group, and most preferably a thiazolyl group. It is.
  • the “monocyclic or condensed polycyclic heteroaryl group which may have a substituent” in the definition of E above includes “excluding an unsubstituted thiazol-2-yl group”.
  • the “monocyclic or condensed polycyclic heteroaryl group optionally having substituent (s)” is most preferably a substituted thiazolyl group.
  • the power S “substituted thiazolyl group” is preferably “monosubstituted thiazole-2-y”. And a di-substituted thiazol-2-yl group, more preferably a di-substituted thiazol-2-yl group.
  • a monocyclic or condensed polycyclic heteroaryl group which may have a substituent is a force S.
  • "Disubstituted thiazol-2-yl group” is particularly preferable.
  • the following “Substituent group S—5e” is a group selected from the group consisting of 4-[(1,1-dimethyl) ethyl] -5-[(2,2-dimethyl) propionyl] thiazole-2- Yl group.
  • the compound represented by the above general formula (I) is preferably a compound other than “substituted benzoic acid derivative represented by the following general formula (X_l)”.
  • R 1001 has the following general formula (X-2):
  • R 1Q ° 3 R 1QQ4 and R 1Q ° 5 are each independently a hydrogen atom, an alkyl group having 16 carbon atoms or an alkoxy group having 16 carbon atoms, and R 1009 and R 1010 are each independently hydrogen.
  • R 1D ° 2 represents a hydrogen atom, a lower alkyl group having 16 carbon atoms which may be substituted, an aryl group having 6 12 carbon atoms which may be substituted, or a carbon atom having 4 11 carbon atoms which may be substituted.
  • ⁇ °° ⁇ represents a carboxyl group which may be esterified or amidated.
  • the compound represented by the above general formula (I) can form a salt.
  • a metal salt such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, or an ammonium salt
  • Ammonium salts such as methionoleammonium salt, dimethylammonium salt, trimethylammonium salt, and dishexylhexylammonium salt can be mentioned.
  • a basic group for example, Mineral salts such as hydrochloride, bromate, sulfate, nitrate and phosphate, or methanesulfonate, benzenesulfonate, paratoluenesulfonate, acetate, propionate, tartrate, fumarate
  • Organic salts such as acid salts, maleates, malates, oxalates, succ
  • the compound represented by the above general formula (I) or a salt thereof exists as a hydrate or a solvate. May be present.
  • the active ingredient of the medicament of the present invention any of the above substances may be used.
  • the compound represented by the general formula (I) may have one or more asymmetric carbon atoms, and may exist as a stereoisomer such as an optically active diastereomer.
  • pure forms of stereoisomers, optical enantiomers or any mixture of diastereomers, racemates and the like may be used.
  • the compound represented by the general formula (I) when it has, for example, a 2-hydroxypyridine structure, it may exist as a 2-pyridone structure which is a tautomer thereof (tautomer).
  • a tautomer in a pure form or a mixture thereof may be used.
  • the configuration When the compound represented by the general formula (I) has an olefinic double bond, the configuration may be any of the Z configuration and the E configuration. Geometric isomers having such an arrangement or a mixture thereof may be used.
  • R and R 1Q1 represent the same meaning as in the definition of deprotection and functional group modification (1) or an alkoxya group such as a methoxymethyl group, etc., and R 1Q1 is hydrogen in the definition of the general formula (I).
  • Halogen atom preferably represents a midoxy group which may be substituted with a chlorine atom, etc.
  • This reaction is carried out in the presence of an acid halogenating agent or a dehydrating condensing agent, in the presence or absence of a base, in a solvent-free or non-protonic solvent at 0 ° C to 180 ° C.
  • Carpoimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diphenylphosphoryl azide and the like can be mentioned.
  • the base include inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydrogencarbonate, and organic bases such as pyridine, triethylamine, N, N-ethylethylamine.
  • Examples of aprotic solvents include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, benzene, tolene, monochlorobenzene, o-dichlorobenzene, N, N-dimethylinoformamide, and N-methylpyrrolid.
  • aprotic solvents include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, benzene, tolene, monochlorobenzene, o-dichlorobenzene, N, N-dimethylinoformamide, and N-methylpyrrolid.
  • an acid halogenating agent tonolenene, monochlorobenzene, and o-dichlorobenzene are particularly preferable.
  • Suitable reaction conditions when G is a hydroxy group include, for example, “Archiv der Pharmazie”, (Germany), 1989, Vol. No., p. 3-6. Can be used.
  • the types of the carboxylic acid derivative (1) and the amine (2) are not particularly limited, and may be newly synthesized with appropriate reference to a known production method in the literature, or a commercially available reagent may be obtained and used in the above reaction. it can.
  • the final target compound (4) can be produced by performing a deprotection reaction and / or a functional group modification reaction in this step.
  • the reaction is performed using various known methods. Examples of the deprotection reaction and the functional group modification reaction include, for example, “Protective 'Gnorape''in'” edited by Theodora W. Green, Peter G. M. M. Putt (Peter GM Wuts).
  • the compound represented by the general formula (I) produced by the above method can be obtained by a method known to those skilled in the art, for example, extraction, precipitation, fraction chromatography, fractional crystallization, suspension washing, recrystallization and the like. Can be used for isolation and purification. Also, pharmacologically acceptable salts of the compound of the present invention, and hydrates and solvates thereof, can be produced by methods known to those skilled in the art.
  • the compound represented by the general formula (I) activates both NF- ⁇ B and AP-1 It has an inhibitory action and is used as an active ingredient of a medicament for preventing and / or treating Alzheimer's disease or a medicament for preventing and / or treating epilepsy.
  • the prevention and / or treatment of Alzheimer's disease includes A / 3 accumulation inhibitory action, neuronal cell death inhibitory action, cerebral atrophy inhibitory action, neurofibrillary tangle change inhibitory action, dementia ameliorating action, etc. And must be interpreted in the broadest sense and not in any sense in a limited sense.
  • prevention and Z or treatment of epilepsy refers to epileptic seizure inhibitory actions such as tonic-clonic seizures, absence seizures, and myoclonic seizures; It must be interpreted in the broadest sense, including the effect of suppressing death, etc., and should not be interpreted in any limited manner.
  • GSK 3 glycostyrene kinase-3 beta
  • MOLT-4F cells human leukemia cells
  • GSK3 / 3 is also known to be inhibited by lithium, and it is known that lithium has an antidepressant effect. If the antidepressant effect of lithium is due to inhibition of GSK33, the compounds of the present invention can be expected to be used as antidepressants.
  • the active ingredient of the medicament of the present invention is selected from the group consisting of compounds represented by the general formula U), pharmacologically acceptable salts thereof, and hydrates and solvates thereof.
  • One or more of the substances can be used.
  • the above-mentioned substance itself may be used as the medicament of the present invention, but preferably, the medicament of the present invention is combined with one or more pharmaceutically acceptable preparations of the above-mentioned substance which is an active ingredient.
  • a pharmaceutical composition comprising: In the above pharmaceutical composition, the ratio of the active ingredient to the pharmaceutical additive is about 1% to 90% by weight.
  • the medicament of the present invention can be administered, for example, as a pharmaceutical composition for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids. Or injection, infusion for intravenous, intramuscular, or subcutaneous administration, It can also be administered as a pharmaceutical composition for parenteral administration such as suppositories, transdermal absorption agents, transmucosal absorption agents, nasal drops, ear drops, eye drops, and inhalants. A preparation prepared as a pharmaceutical composition in powder form may be dissolved at the time of use and used as an injection or infusion. For the production of pharmaceutical compositions, solid or liquid pharmaceutical additives can be used.
  • Pharmaceutical additives may be either organic or inorganic. That is, when an oral solid preparation is manufactured, excipients and, if necessary, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. are added to the active ingredient, and then tablets are prepared in the usual manner. Preparations such as coated tablets, granules, powders, capsules and the like can be prepared. Examples of the excipient used include lactose, sucrose, sucrose, glucose, corn starch, starch, talc, sorbite, crystalline cellulose, dextrin, kaolin, calcium carbonate, silicon dioxide, and the like.
  • binder examples include polyvinylinoleanolone, polyvinylinoleatenole, etinoresenorelose, methinoresenolerose, gum arabic, tragacanth, gelatin, shellac, hydroxypropinoresolenoose, and hydroxyaluminum. Doxypropyl methylcellulose, canolecum citrate, dextrin, pectin and the like can be mentioned.
  • lubricant examples include magnesium stearate, talc, polyethylene glycol, silica, and hardened spot oil. Any coloring agent that is normally permitted to be added to pharmaceuticals can be used.
  • cocoa powder As a flavoring agent, cocoa powder, heart-shaped brain, aromatic acid, heart-shaped oil, dragon brain, cinnamon powder and the like can be used. These tablets and granules can be sugar-coated, gelatin-coated and optionally coated as required. Further, a preservative, an antioxidant, and the like can be added as needed.
  • liquid preparations for oral administration such as emulsions, syrups, suspensions and solutions
  • inert diluents such as water or vegetable oils
  • the preparation can contain adjuvants such as wetting agents, suspending aids, sweetening agents, fragrances, coloring agents or preservatives.
  • the liquid preparation may be filled into capsules of an absorbable substance such as gelatin.
  • Preparations for parenteral administration include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin Can be.
  • As the base used in the manufacture of suppositories for example, cocoa butter, emulsified cocoa butter, lauric fat, and witetbsol can be mentioned.
  • the method for preparing the preparation is not particularly limited, and any method commonly used in the art can be used.
  • diluents such as water, ethyl alcohol, macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid and sodium hydroxide; PH adjusters and buffers such as sodium taenoate, sodium acetate and sodium phosphate; stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thiodaricholic acid and thiolactic acid can be used.
  • a sufficient amount of salt, bud sugar, mannitol, or glycerin to prepare an isotonic solution may be incorporated into the preparation. Agents and the like can also be used.
  • ointments for example, pastes, creams and gels, commonly used bases, stabilizers, wetting agents, preservatives, etc. can be added as necessary, and the ingredients can be formulated in a conventional manner. They can be formulated by mixing.
  • the base for example, white cellulose, polyethylene, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicon and bentonite can be used.
  • a preservative methyl paraoxybenzoate, ethyl ethyl paraoxybenzoate, propyl paraoxybenzoate and the like can be used.
  • the preparation When the preparation is in the form of a patch, the above-mentioned ointment, cream, gel, paste or the like can be applied to a usual support in a conventional manner.
  • a woven or non-woven fabric made of cotton, staple fiber and chemical fiber; a film or a foam sheet made of soft vinyl chloride, polyethylene, polyurethane or the like can be preferably used.
  • the dose of the medicament of the present invention is not particularly limited.
  • the weight of the substance, which is an active ingredient is usually 0.01 to 50,000 mg per day for an adult. It is preferable to increase or decrease the dose according to the age, disease state and symptoms of the patient.
  • the above-mentioned daily dose may be administered once a day, or divided into two or three times a day at appropriate intervals, or may be administered intermittently every few days.
  • the weight of the above substance, which is an active ingredient is about 0.001 to 100 mg per adult.
  • the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.
  • the compound numbers correspond to the compound numbers shown in the above table.
  • a compound which was purchased from a commercially available reagent and subjected to the test as it is was included.
  • For such compounds indicate the reagent vendor and the code number listed on the tag.
  • Example 3 The same operation as in Example 3 was carried out using 5-chloromouth salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 5 when the method of Example 5 was cited, an organic base such as pyridin or triethylamine was used as the base. In addition, solvents such as dichloromethane, tetrahydrofuran, and benzene were used as reaction solvents.
  • Example 6 Preparation of compound No. 6 The same operation as in Example 3 was carried out using 5-bromosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • This compound could also be obtained by the following production method.
  • Example 3 The same operation as in Example 3 was performed using 5-odesalicylic acid and 3,5-bis (trifluoromethyl) farin as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 5-nitrosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound. Yield: 57.2%
  • Example 3 The same operation as in Example 3 was carried out using 5-cyanosalicylic acid and 3,5-bis (trifnoroleolomethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same procedure as in Example 3 was carried out using 5-methylsalicylic acid and 3,5-bis (trifnorelomethyl) aniline as starting materials to obtain the title compound.
  • Example 12 (3) when the production method of Example 12 (3) was cited, phosphorus oxychloride was used as the acid halogenating agent. Pyridine was used as the base. As a reaction solvent, a solvent such as dichloromethane or tetrahydrofuran was used alone or as a mixture.
  • N— [3,5-bis (trifnorolelomethynole) phenyl] -12-hydroxy-1-5-bendoamide (Compound No. 7; 475 mg, 1 mmo 1), styrene (130 mg, 1 25 mmo 1), palladium acetate (4.5 mg, 0.02 mmo l), tris (ortho-tolyl) phosphine (12.2 mg, 0.04 mmo 1), disopropylamine (388 mg, A mixture of 3 mmo1) and N, N-dimethylformamide (2 mL) was heated to reflux for 8 hours. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate.
  • Example 12 using N- [3,5-bis (trifluoromethyl) phenyl] -12-hydroxy-5- (phenylethynyl) benzamide (Compound No. 22) as a raw material The same operation as in (4) was performed to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 2-hydroxy-5- (trifluoromethyl) benzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound. .
  • Example 3 The same operation as in Example 3 was performed using 5-methoxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-isobutyryl-1-methoxybenzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 4-hydroxyisophthalic acid-1-methyl ester and 3,5-bis (trifluoromethyl) aniline as raw materials to obtain the title compound.
  • Example 36 when the method of Example 36 was cited, an inorganic base such as sodium hydroxide or potassium carbonate was used as the base.
  • a reaction solvent a solvent such as water, methanol, ethanol, or tetrahydrofuran was used alone or as a mixture.
  • N-dimethylformamide 10 OmL
  • N- [3,5_bis (trifluoromethyl) phenyl) under ice-cooling.
  • N, N-Dimethylformamide (1) of —4-hydroxyisophthalamic acid methyl ester Compound No. 35; 8.15 g, 2 Ommo 1 0 OmL
  • benzyl bromide 4.
  • Example 36 The same operation as in Example 36 was performed using 4-benzyloxy-N- [3,5-bis (trifluoromethyl) phenyl] isophthalamic acid methyl ester as a starting material to obtain the title compound.
  • the reaction mixture was poured into water and extracted with ethyl acetate.
  • the ethyl acetate layer was washed successively with dilute hydrochloric acid, water, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the title compound was obtained as a white solid (165 mg, 64.9%).
  • Example 38 (3) when the method of Example 38 (3) was cited, an organic base such as pyridine or triethylamine was used as the base.
  • a reaction solvent a solvent such as dichloromethane, tetrahydrofuran, or the like was used alone or as a mixture.
  • Example 38 As in Example 38 (3) using 4-benzyloxy-1-N- [3,5-bis (trifluoromethyl) phenyl] isophthalamic acid (compound of Example 38 (2)) and piperidine as raw materials The operation was performed to obtain the title compound.
  • Example 12 (3) The same operation as in Example 12 (3) was carried out using 2-methoxy-1-5-sulfamoylbenzoic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 38 The same operation as in Example 38 (4) was carried out using N- [3,5-bis (trifluoromethyl) phenyl] -2-hidoxy-5-trobenzamide (Compound No. 8) as the starting material. The title compound was obtained.
  • Example 3 The same operation as in Example 3 was performed using 5-dimethylaminosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-[(4-nitrotropenyl) diazenyl] salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 36 The same operation as in Example 36 was carried out using 4-acetylamino-5-chloro-2-methylbenzoic acid methyl ester as a starting material to obtain the title compound.
  • Example 12 The same operation as in Example 12 (3) was carried out using 4-acetinoleamino-5-chloro mouth_2-methoxybenzoic acid and 3,5-bis (trifluoromethyl) aniline as raw materials. The title compound was obtained.
  • Example 3 The same operation as in Example 3 was carried out using 4-monosalicylic acid and 3,5_bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 6-hydroxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 4-methylsalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same procedure as in Example 3 was performed using 5-promo 4-hydroxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound. Yield: 82.4%
  • Example 3 The same operation as in Example 3 was performed using 4-hydroxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as raw materials to obtain the title compound.
  • Example 3 The same procedure as in Example 3 was carried out using 3,5-dichloromouth salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 3-methylsalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 3-methoxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same procedure as in Example 3 was performed using 5-[(1,1,3,3-tetramethyl) butyl] salicylic acid and 3,5-bis (trifluoromethyl) urin as starting materials to give the title compound I got
  • Example 3 The same operation as in Example 3 was performed using 3,5-bis [(1,1-dimethyl) ethyl] salicylic acid and 3,5_bis (trifluoromethyl) aniline as raw materials to obtain the title compound. .
  • Example 3 The same operation as in Example 3 was performed using 6-fluorosalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same procedure as in Example 3 was carried out using 3-cyclomouth salicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 4-methoxysalicylic acid and 3,5-bis (trifoleolomethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same procedure as in Example 3 was carried out using 6-methoxysalicylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 1-hydroxynaphthalene-12-hydroxycarboxylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 3-hydroxynaphthalene-1-carboxylic acid and 3,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same procedure as in Example 3 was carried out using 4-bromo-3-hydroxythiophene 121, carboxylic acid and 3,5-bis (trifluoromethyl) aerine as starting materials to obtain the title compound.
  • 4-bromo-3-hydroxythiophene 121, carboxylic acid and 3,5-bis (trifluoromethyl) aerine as starting materials to obtain the title compound.
  • Example 75 When the production method of Example 75 is cited in the following Examples, phosphorus oxychloride was used as a condensing agent (acid halogenating agent). Pyridine was used as the base. As a reaction solvent, a solvent such as dichloromethane or tetrahydrofuran was used alone or as a mixture.
  • Example 75 The same procedure as in Example 75 was carried out using 3-hydroxypyridine_2-carboxylic acid and 3,5-bis (trifluoromethyl) farin as starting materials to obtain the title compound.
  • Example 77 The same operation as in Example 77 was carried out using 3,5-bis (trifluoromethyl) phenylisocyanate and oxindole as the starting materials to obtain the title compound. Yield: 44.8%
  • Example 77 The same operation as in Example 77 was carried out using 3,5-bis (trifluoromethyl) phenylisocyanate and 5- chlorooxaindole as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 3-hydroxyquinoxaline-12-carboxylic acid and 3,5_bis (trifluoromethyl) aniline as raw materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 5-chlorosalicylic acid and 2,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 5-bromosalicylic acid and 2,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 5-methylsalicylic acid and 2,5-bis (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-chloro salicylic acid and 3-fluoro-5- (trifluoromethyl) farin as starting materials to obtain the title compound.
  • Example 86 Preparation of compound No. 86 The same operation as in Example 3 was carried out using 5-bromosalicylic acid and 3-bromo-5- (trifnoroleolomethyl) aniline as the starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-cyclosalicylic acid and 2-fluoro-5- (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-chloromouth salicylic acid and 2-chloro-5_ (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 5-bromosalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-chlorosalicylic acid and 2-nitro-5- (trifluoromethyl) farin as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-cyclomouth salicylic acid and 2-methyl-5- (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 5-bromosalicylic acid and 3-methoxy-1-5- (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 5-bromosalicylic acid and 2-methoxy-5- (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-chlorosalicylic acid and 2-methoxy-5- (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-cyclosalicylic acid and 2-methylsulfur-1-yl-5- (trifluoromethyl) farin as starting materials to obtain the title compound. Yield: 79.2%
  • Example 3 The same operation as in Example 3 was carried out using 5-bromosalicylic acid and 2_ (1-pyrrolidyl) -15- (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was carried out using 5-bromosalicylic acid and 2-morpholino 5- (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same procedure as in Example 3 was carried out using 5-trosalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 5-methylsalicylic acid and 2-chloro-5- (trifluoromethyl) farin as starting materials to obtain the title compound.
  • Example 3 The same operation as in Example 3 was performed using 5-methoxysalicylic acid and 2-chloro-5- (trifluoromethyl) aniline as a raw material to obtain the title compound.

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Abstract

L'invention concerne des médicaments prophylactiques ou thérapeutiques destinés aux maladies neurodégénératives tels que la maladie d'Alzheimer. Les principes actifs de ces médicaments sont sélectionnés dans le groupe constitué par les composés de la formule générale (I), des sels pharmacologiquement acceptables de ceux-ci, ainsi que des hydrates et des solvates. Dans cette formule, A représente hydrogène ou acétyle, E représente 2,5- ou 3,5-phényle disubstitué ou un groupe hétéroaryle polycyclique monocyclique ou condensé (à l'exclusion de (1) hétéroaryle polycyclique condensé dont le cycle benzénique est directement lié au groupe CONH-, (2) thiazol-2-yl non substitué, et (3) benzothiazol-2-yl non substitué) ; et Z représente arène pouvant avoir un substituant en plus des groupes représentés par la formule générale : O-A (dans laquelle A est tel que défini ci-dessus) et CONH-E (dans laquelle E est tel que défini ci-dessus), ou un hétéroarène pouvant avoir un substituant en plus des groupes représentés par la formule générale : -O-A (dans laquelle A est tel que défini ci-dessus) et CONH-E (dans laquelle E est tel que défini ci-dessus).
PCT/JP2003/007128 2002-06-11 2003-06-05 Traitements des maladies neurodegeneratives WO2003103657A1 (fr)

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US10/516,293 US20060035944A1 (en) 2002-06-11 2003-06-05 Remedies for neurodegenerative diseases
CA002488979A CA2488979A1 (fr) 2002-06-11 2003-06-05 Medicament pour le traitement des maladies neurodegeneratives
EA200500006A EA011707B1 (ru) 2002-06-11 2003-06-05 Лекарственное средство для лечения нейродегенеративных заболеваний
AU2003242124A AU2003242124A1 (en) 2002-06-11 2003-06-05 Medicament for treatment of neurodegenerative diseases
EP03730838A EP1555018A4 (fr) 2002-06-11 2003-06-05 Traitements des maladies neurodegeneratives
JP2004510776A JP4635130B2 (ja) 2002-06-11 2003-06-05 神経変性疾患治療剤
US12/123,934 US20080234233A1 (en) 2002-06-11 2008-05-20 Medicament for treatment of neurodegenerative diseases

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JP2002169640 2002-06-11

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6908923B2 (en) 2001-12-21 2005-06-21 Cytokinetics, Inc. Compositions and methods for treating heart failure
EP1700856A1 (fr) * 2003-12-26 2006-09-13 Kyowa Hakko Kogyo Co., Ltd. Derive de thiazole
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US7053094B2 (en) 2001-12-21 2006-05-30 Cytokinetics, Inc. Compositions and methods for treating heart failure
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US7638536B2 (en) 2002-01-18 2009-12-29 Astellas Pharma Inc. 2-Acylaminothiazole derivative or salt thereof
US8765764B2 (en) 2002-01-18 2014-07-01 Astellas Pharma, Inc. 2-acylaminothiazole derivative or salt thereof
US7863298B2 (en) 2003-10-14 2011-01-04 Exelixis, Inc. Bridged ring structures as pharmaceutical agents
EP1700856A4 (fr) * 2003-12-26 2009-06-24 Kyowa Hakko Kirin Co Ltd Derive de thiazole
JPWO2005063743A1 (ja) * 2003-12-26 2007-07-19 協和醗酵工業株式会社 チアゾール誘導体
EP1700856A1 (fr) * 2003-12-26 2006-09-13 Kyowa Hakko Kogyo Co., Ltd. Derive de thiazole
NO338017B1 (no) * 2003-12-26 2016-07-18 Kyowa Hakko Kirin Co Ltd Tiazolderivater, farmasøytiske preparater inneholdende slike, og anvendelse derav
US7671058B2 (en) 2006-06-21 2010-03-02 Institute Of Medicinal Molecular Design, Inc. N-(3,4-disubstituted phenyl) salicylamide derivatives
US10640457B2 (en) 2009-12-10 2020-05-05 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase activators and uses thereof
US11034647B2 (en) 2009-12-10 2021-06-15 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase activators and uses thereof
JP2014501763A (ja) * 2010-12-22 2014-01-23 ザ トラスティーズ オブ コロンビア ユニヴァーシティ イン ザ シティ オブ ニューヨーク ヒストンアセチル基転移酵素モジュレーターおよびその使用
US9969677B2 (en) 2010-12-22 2018-05-15 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase modulators and uses thereof
JP2018016647A (ja) * 2012-05-08 2018-02-01 エアロミクス・インコーポレイテッドAeromics,Inc. 新規方法
JP2015520151A (ja) * 2012-05-08 2015-07-16 エアロミクス・リミテッド・ライアビリティ・カンパニーAeromics,LLC 新規方法
CN111419830A (zh) * 2013-03-12 2020-07-17 比皮艾思药物研发有限公司 用于预防或治疗癫痫和癫痫相关综合征的苯基烷基氨基甲酸酯化合物
CN111419830B (zh) * 2013-03-12 2024-01-30 比皮艾思药物研发有限公司 用于预防或治疗癫痫和癫痫相关综合征的苯基烷基氨基甲酸酯化合物
JP2016536370A (ja) * 2013-11-06 2016-11-24 エアロミクス・インコーポレイテッドAeromics,Inc. 新規製剤
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TW200402290A (en) 2004-02-16
EP1555018A4 (fr) 2009-01-07
CA2488979A1 (fr) 2003-12-18
CN1658858A (zh) 2005-08-24
AU2003242124A1 (en) 2003-12-22
JPWO2003103657A1 (ja) 2005-10-06
US20080234233A1 (en) 2008-09-25
EA011707B1 (ru) 2009-04-28
CN100490793C (zh) 2009-05-27
EA200500006A1 (ru) 2005-08-25
US20060035944A1 (en) 2006-02-16
TWI280127B (en) 2007-05-01
JP4635130B2 (ja) 2011-02-16
EP1555018A1 (fr) 2005-07-20

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